1-amino-alkylcyclohexane NMDA receptor antagonists

ABSTRACT

Certain 1-aminoalkylcyclohexanes are systemically-active uncompetitive NMDA receptor antagonists having rapid blocking/unblocking kinetics and strong voltage-dependency and are therefore useful in the alleviation of conditions resulting from disturbances of glutamatergic transmission giving them a wide range of utility in the treatment of CNS disorders involving the same, as well as in non-NMDA indications, due to their immunomodulatory, antimalarial, anti-Borna virus, and anti-Hepatitis C activities and utilities. Pharmaceutical compositions thereof and a method-of-treating conditions which are alleviated by the employment of an NMDA receptor antagonist, as well as the aforementioned non-NMDA indications, and a method for the preparation of the active 1-aminoalkylcyclohexane compounds involved.

The present application is a continuation-in-part of our prior-filedcopending application Ser. No. 09/048,575 filed Mar. 26, 1998, nowabandoned, which in turn is a division of our prior-filed applicationSer. No. 08/885,944, filed Jun. 30, 1997, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

1-Amino-alkylcyclohexane compounds which are systemically-active as NMDAreceptor antagonists, pharmaceutical compositions comprising the same,method of preparation thereof, and method of treating CNS disorderswhich involve disturbances of glutamatergic transmission therewith.

2. Prior Art

Antagonism of glutamate receptors of the N-methyl-D-aspartate (NMDA)type has a potentially wide range of therapeutic applications [19].Functional inhibition of NMDA receptors can be achieved through actionsat different recognition sites such as the primary transmitter site,strychnine-insensitive glycine site (glycine_(B)), polyamine site, andphencyclidine site located inside the cation channel. The NMDA receptorchannel blockers act in an uncompetitive "use-dependent" manner, meaningthat they usually only block the channel in the open state. Thisuse-dependence has been interpreted by many to mean that strongeractivation of the receptor should lead to a greater degree ofantagonism. Such a mode of action has further been taken to imply thatthis class of antagonist may be particularly useful when overactivationof NMDA receptors can be expected, such as in epilepsy, ischaemia, andtrauma. However, initial clinical experience with the selective, highaffinity, strongly use-dependent uncompetitive NMDA receptor antagonist(+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate((+)-MK-801) has been disappointing. Namely, therapeutic efficacy inepilepsy was poor while some psychotropic side effects were apparent attherapeutic doses. These observations, together with the fact thatphencyclidine abusers experience similar psychotropic symptoms, has ledto the conclusion that uncompetitive antagonism of NMDA receptors maynot be a promising therapeutic approach.

However, the use of more elaborate electrophysiological methodsindicates that there is no equality between different uncompetitiveantagonists since factors such as the speed of receptor blockade (on-offkinetics) and the voltage-dependence of this effect may determine thepharmacodynamic features in vivo, i.e., therapeutic safety as well.Paradoxically, agents with low to moderate, rather than high, affinitymay be desirable. Such findings -triggered a reconsideration of theconcept of uncompetitive antagonism of NMDA receptors in drugdevelopment [19, 22]. At present, many such agents are at differentstages of development, e.g., carvedilol, ADCI, ES 242S, remacemide,felbamate, and budipine. On the other hand, uncompetitive NMDA receptorantagonists, such as amantadine and memantine--which fulfill the abovecriteria--have been used clinically for several years in the treatmentof Parkinson's disease and dementia respectively, and do indeed rarelyproduce side effects at the therapeutic doses used in their respectiveindications.

In view of the above mentioned evidence, we have developed a series ofnovel uncompetitive NMDA receptor antagonists based on the1-aminoalkylcyclohexane structure. The present study was devoted tocompare the NMDA receptor antagonistic properties of these1-aminoalkylcyclohexane derivatives in receptor-binding assays, patchclamp experiments, excitotoxicity in vitro, three convulsion models, andtwo models of motor impairment. The substitutions of these1-aminoalkylcyclohexanes are detailed in Table 6.

THE PRESENT INVENTION

It has now been found that certain 1-aminoalkylcyclohexanes havepronounced and unpredictable NMDA receptor antagonistic activity. Owingto the aforementioned property, the substances are suited for thetreatment of a wide range of CNS disorders which involve disturbances ofthe glutamatergic transmission, preferably in the form of apharmaceutical composition thereof wherein they are present togetherwith one or more pharmaceutically-acceptable diluents, carriers, orexcipients.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novel pharmaceuticalcompounds which are 1-aminoalkylcyclohexane NMDA receptor antagonistsand pharmaceutical compositions thereof. It is a further object of theinvention to provide a novel method of treating, eliminating,alleviating, palliating, or ameliorating undesirable CNS disorders whichinvolve disturbances of glutamatergic transmission by the employment ofsuch a compound of the invention or a pharmaceutical compositioncontaining the same. An additional object of the invention is theprovision of a process for producing the said 1-aminoalkylcyclohexaneactive principles. Yet additional objects will become apparenthereinafter, and still further objects will be apparent to one skilledin the art.

SUMMARY OF THE INVENTION

What we therefore believe to be comprised by our invention may besummarized inter alia in the following words:

A 1-aminoalkylcyclohexane compound selected from the group consisting ofthose of the formula ##STR1## wherein R* is --(CH₂)_(n) --(CR⁶ R⁷)_(m)--NR⁸ R⁹

wherein n+m=0, 1, or 2

wherein R¹ through R⁷ are independently selected from the groupconsisting of hydrogen and lower-alkyl (1-6C), at least R¹, R⁴, and R⁵being lower-alkyl, and wherein R⁸ and R⁹ are independently selected fromhydrogen and lower-alkyl (1-6C) or together represent lower-alkylene--(CH₂)_(x) -- wherein x is 2 to 5, inclusive, and enantiomers, opticalisomers, hydrates, and pharmaceutically-acceptable salts thereof;

such a compound wherein R¹ through R⁵ are methyl;

such a compound wherein R¹ is ethyl;

such a compound wherein R² is ethyl;

such a compound wherein R³ is ethyl;

such a compound wherein R⁴ is ethyl;

such a compound wherein R⁵ is ethyl;

such a compound wherein R⁵ is propyl;

such a compound wherein R⁶ or R⁷ is methyl;

such a compound wherein R⁶ or R⁷ is ethyl; and

such a compound wherein the compound is selected from the groupconsisting of

1-amino-1,3,5-trimethylcyclohexane,

1-amino-1(trans),3(trans),5-trimethylcyclohexane,

1-amino-1(cis),3(cis),5-trimethylcyclohexane,

1-amino-1,3,3,5-tetramethylcyclohexane,

1-amino-1,3,3,5,5-pentamethylcyclohexane,

1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,

1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,

1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane,

1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane,

1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,

1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,

N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,

N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, and

N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine, and hydrates, andpharmaceutically-acceptable salts of any of the foregoing.

Moreover, a method-of-treating a living animal for alleviation of acondition which is alleviated by an NMDA receptor antagonist, or for itsimmunomodulatory, antimalarial, anti-Borna virus, or anti-Hepatitis Ceffect, comprising the step of administering to the said living animalan amount of a 1-aminoalkylcyclohexane compound selected from the groupconsisting of those of the formula ##STR2## wherein R* is --(CH₂)_(n)--(CR⁶ R⁷)_(m) --NR⁸ R⁹

wherein n+m=0, 1, or 2

wherein R¹ through R⁷ are independently selected from the groupconsisting of hydrogen and lower-alkyl (1-6C), wherein R⁸ and R⁹ areindependently selected from hydrogen and lower-alkyl (1-6C) or togetherrepresent lower-alkylene --(CH₂)_(x) -- wherein x is 2 to 5, inclusive,and optical isomers, enantiomers, hydrates, andpharmaceutically-acceptable salts thereof, which is effective for thesaid purpose;

such a method wherein R¹ through R⁵ are methyl;

such a method wherein R¹ is ethyl;

such a method wherein R² is ethyl;

such a method wherein R³ is ethyl;

such a method wherein R⁴ is ethyl;

such a method wherein R⁵ is ethyl;

such a method wherein R⁵ is propyl;

such a method wherein R⁶ or R⁷ is methyl;

such a method wherein R⁶ or R⁷ is ethyl; and

such a method wherein the compound is selected from the group consistingof

1-amino-1,3,5-trimethylcyclohexane,

1-amino-1(trans),3(trans),5-trimethylcyclohexane,

1-amino-1(cis),3(cis),5-trimethylcyclohexane,

1-amino-1,3,3,5-tetramethylcyclohexane,

1-amino-1,3,3,5,5-pentamethylcyclohexane,

1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,

1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,

1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane,

1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane,

1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,

1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,

N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,

N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, and

N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine, and hydrates andpharmaceutically-acceptable salts of any of the foregoing; and

such a method wherein the compound is administered in the form of apharmaceutical composition thereof comprising the compound incombination with one or more pharmaceutically-acceptable diluents,excipients, or carriers.

Further, an NMDA-receptor antagonist pharmaceutical compositioncomprising an effective NMDA-receptor antagonistic amount, or aneffective immunomodulatory, antimalarial, anti-Borna virus, oranti-Hepatitis C amount, of a 1-aminoalkylcyclohexane compound selectedfrom the group consisting of those of the formula ##STR3## wherein R* is--(CH₂)_(n) --(CR⁶ R⁷)_(m) --NR⁸ R⁹

wherein n+m=0, 1, or 2

wherein R¹ through R⁷ are independently selected from the groupconsisting of hydrogen and lower-alkyl (1-6C), at least R¹, R⁴, and R⁵being lower-alkyl, and wherein R⁸ and R⁹ are independently selected fromhydrogen and lower-alkyl (1-6C) or together represent lower-alkylene--(CH₂)_(x) -- wherein x is 2 to 5, inclusive, and optical isomers,enantiomers, hydrates, and pharmaceutically-acceptable salts thereof, incombination with one or more pharmaceutically-acceptable diluents,excipients, or carriers;

such a pharmaceutical composition wherein R¹ through R⁵ are methyl;

such a pharmaceutical composition wherein R¹ is ethyl;

such a pharmaceutical composition wherein R² is ethyl;

such a pharmaceutical composition wherein R³ is ethyl;

such a pharmaceutical composition wherein R⁴ is ethyl;

such a pharmaceutical composition wherein R⁵ is ethyl;

such a pharmaceutical composition wherein R⁵ is propyl;

such a pharmaceutical composition wherein R⁶ or R⁷ is methyl;

such a pharmaceutical composition wherein R⁶ or R⁷ is ethyl;

such a pharmaceutical composition wherein the compound is selected fromthe group consisting of

1-amino-1,3,5-trimethylcyclohexane,

1-amino-1(trans),3(trans),5-trimethylcyclohexane,

1-amino-1(cis),3(cis),5-trimethylcyclohexane,

1-amino-1,3,3,5-tetramethylcyclohexane,

1-amino-1,3,3,5,5-pentamethylcyclohexane,

1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,

1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,

1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane,

1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane,

1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,

1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,

N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,

N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, and

N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine, and hydrates andpharmaceutically-acceptable salts of any of the foregoing.

DETAILED DESCRIPTION OF THE INVENTION

The following details and detailed Examples are given by way ofillustration only, and are not to be construed as limiting. ##STR4##Preparation of 3-propyl-5,5-dimethyl-2-cyclohexene-1-one (1-7)

A solution of 3-ethoxy-5,5-dimethyl-2-cyclohexene-1-one [1] (5.04 g, 30mmol) in ether was added dropwise to a stirred solution ofpropylmagnesium iodide prepared from 90 mg of magnesium and 90 mmol of1-iodopropane in 60 ml of ether. After being stirred for 1 h at ambienttemperature, the reaction mixture was treated with 5% H₂ SO₄ solution.The organic phase was separated, washed with saline, dried over MgSO₄and evaporated to give a crude oil which was separated on a silica gelcolumn, eluting with hexane-ethyl acetate mixture. Cyclohexenone (1-7)was obtained as a colourless oil (2.0 g, 70%). ¹ H NMR (CDCl₃, TMS)δ:0.92 (3H, t, J=7 Hz); 1.03 (6H,s); 1.3-1.75 (2H,m); 2.16 (2H, t, J=7Hz); 2.17 (2H, d, J=1.5 Hz); 2.21 (2H,s) and 5.87 ppm (1H, t, J=1.5 Hz).

Such known cyclohexenones 1 were used to prepare compounds 2:

1-1 (R¹ =R² =R³ =H) [commerc. available],

1-2 (R³ =Me)* [commerc. available],

1-3 (R² =R³ =Me) [commerce available],

1-4 (R¹ =R² =Me) [2],

1-5 (R¹ =R² =R³ =Me) [commerc. available],

1-6 (R¹ =R² =Me, R³ =Et) [3].

*R^(n) =H, if omitted

Other starting materials 1 are prepared in the same or similar manner.

General procedure for preparation of cyclohexanones 2.

Anhydrous copper (1) chloride (7.5 mmol) was added to a cooled solutionof alkylmagnesium iodide (15-18 mmol) in ether. The mixture was stirredin an inert atmosphere for 5 minutes and a solution of2-cyclohexene-1-one 1 (10 mmol) in ether was added dropwise keeping thetemperature below -5° C. After the addition of ketone was completed, thereaction mixture was stirred for 1 hour and carefully neutralized withsaturated aqueous NH₄ Cl solution. Traditional workup for Grignardreactions gave crude material which was separated on a silica gelcolumn, eluting with a petroleum ether-ethyl acetate mixture. Thecyclohexanones 2 were obtained as oils.

Yields and ¹ H NMR spectral data of compounds 2 are given in Table 1.

Such known cyclohexanones 2 were used to prepare compounds 3.

2-1 (R⁴ =Me)* [commerc. available],

2-2 (R⁴ =Et) [4],

2-3 (R⁴ =Pr) [5],

2-4 (R³ =R⁴ =Me) [6],

2-5 (R³ =Me, R⁴ =Et) [7],

2-6 (R³ =Me, R⁴ =Pr) [8],

2-7 (R¹ =R⁴ =Me) [9],

2-8 (R² =R³ =R⁴ =Me) [10],

2-9 (R² =R³ =Me, R⁴ =Et) [11],

2-13 (R¹ =R² =R³ =R⁴ =Me) [commerc. available],

2-14 (R¹ =R² =R³ =Me, R⁴ =Et) [10],

2-15 (R¹ =R² =R³ =Me, R⁴ =Pr) [10].

*R^(n) =H, if omitted.

Other intermediate cyclohexanones 2 are prepared in the same or asimilar manner. Cyclohexanones 2 were used to prepare compounds 3:

General procedure for preparation of alkylcyclohexanols 3.

An etheral solution of alkylmagnesium iodide (3-4 equivalents) was addeddropwise to a cooled solution of cyclohexanone 2 in ether. The mixturewas stirred for 1 hour at ambient temperature and carefully destroyedwith saturated aqueous ammonium chloride. Traditional workup forGrignard reactions gave mixtures of diastereomeric alcohols 3, whichwere separated on a silica gel column eluting with petroleum ether-ethylacetate.

Yields and ¹ H NMR spectral data of compounds 3 are given in Table 2.

Such known cyclohexanols 3 were used to prepare compounds 4:

3-1 ((R³)(R⁴)=R⁵ =Me)* [9], i.e., R³ or R⁴ and R⁵ are Me.

3-4 (R³ =R⁴ =Me, R⁵ =Me) [12],

3-5 (R³ =R =Me, R⁴ =Et) [13],

3-7 (R¹ =R⁴ =R⁵ =Me) [14],

3-8 (R¹ =R³ =R⁴ =R⁵ =Me) [10],

3-13 (R¹ =R² =R³ =R⁴ =R⁵ =Me) [10],

3-14 (R¹ =R² =R³ =R⁴ =Me, R⁵ =Et) [15],

*R^(n) =H, if omitted.

Other intermediate cyclohexenols 3 are prepared in the same or a similarmanner.

General procedure for preparation of 1-alkyl-1-azidocyclohexanes 4.

The alcohol 3 was mixed with 1.7-2 N hydrazoic acid (10-13 equivalents)solution in chloroform, and cooled in an ice bath. A solution of TiCl₄(1.2 equivalents) in chloroform was added dropwise while temperature wasmaintained below 5° C. The mixture was stirred at room temperature for24 hours and passed down a column of alumina, eluting with chloroform.Evaporation of solvent provided diastereomeric azides 4 which werepurified by flash chromatography on silica gel, eluting with lightpetroleum ether.

Yields and ¹ H NMR spectral data of compounds 4 are given in Table 3.

Other intermediate 1-alkyl-1-azidocyclohexanes 4 are prepared in thesame or a similar manner.

Preparation of 1-nitromethyl-3,3,5,5-tetramethylcyclohexene (6).

A solution of 3,3,5,5-tetramethylcyclohexanone (2-13) (1.54 g, 10 mmol)and ethylenediamine (60 mg) in nitromethane (45 ml) was refluxed inargon atmosphere for 25 h. Excess of nitromethane was then removed invacuo and the residue was purified by flash chromatography on silicagel, eluting with hexane-ethyl acetate (6:1). 1.2 g (61%) of 6 wasobtained as an oil.

¹ H NMR (CDCl₃, TMS) δ 0.96 and 1.03 (total 12H, both s, cyclohexane3,5-CH₃); 1.34 (2H, s, 4-CH₂); 1.82 (2H, br s, 6-CH₂); 4.80 (2H, s, CH₂NO₂) and 5.64 ppm (1H, br s, C═C--H).

Preparation of ethyl 3,3,5,5-tetramethylcyclohexylideneacetate (7).

To a stirred solution of triethyl phosphonoacetate (49.32 g, 0.22 mol)in dry THF (180 ml) under argon NaH (8.8 g, 0.22 mol, 60% suspension inmineral oil) was added in small portions while cooling with ice water.Stirring was continued for 1 h at room temperature, then a solution of3,3,5,5-tetramethylcyclohexanone (2-13) (30.85 g, 0.2 mol) was addedover 10 min and the resulting mixture was refluxed for 22 h. It was thenpoured onto ice (400 g), the product was extracted with ether (4*150 ml)and the solution dried over MgSO₄. After concentration in vacuo an oilyresidue was distilled at 145° C. (11 mm) to give 36.8 g (86%) of 6 as anoil.

¹ H NMR (CDCl₃, TMS) δ 0.96 and 0.98 (total 12H, both s, cyclohexane3,5-CH₃); 1.27 (3H, t, CH₃ -ethyl); 1.33 (2H, m, cyclohexane 4-CH₂);1.95 and 2.65 (total 4H, both s, cyclohexane 2,6-CH₂); 4.14 (2H, q, CH₂-ethyl) and 5.69 ppm (1H, s, ═C--H).

Preparation of ethyl 3,3,5,5-tetramethylcyclohexylacetate (8).

Ethyl 3,3,5,5-tetramethylcyclohexylideneacetate (7) (4.48 g, 20 mmol) inethanol (100 ml) was hydrogenated over 10% Pd/C (0.22 g, 5 wt. %) at 10atm for 18 h. Filtration through Celite™ and evaporation afforded 4.28 g(95%) of 8 as an oil.

¹ H NMR (CDCl₃, TMS) δ 0.89 and 1.02 (total 12H, both s, --cyclohexane3,5-CH₃); 1.26 (3H, t, J=7Hz, CH₃ -ethyl); 0.6-1.55 (7H, m, ringprotons); 2.13 (2H, m, 2-CH₂); and 4.12 ppm (2H, q, J=7Hz, CH₂ -ethyl).

Preparation of 2-methyl-(3,3,5,5-tetramethylcyclohexyl)-propan-2-ol (9).

A solution of ethyl 3,3,5,5-tetramethylcyclohexylacetate (8) (2.26 g, 10mmol) in ether (20 ml) was added dropwise to a 2 M methylmagnesiumiodide solution in ether (20 ml) over 15 min, while cooling with icewater. The mixture was refluxed for 2 h, cooled and quenched withsaturated aqueous NH₄ Cl. After traditional workup the product waspurified on silica gel column, eluting with a mixture of hexane-ethylacetate (20:1) to give 1.7 g (80%) of 9 as an oil.

¹ H NMR (CDCl₃, TMS) δ 0.86 and 1.00 (total 12H, both s, cyclohexane3,5-CH₃); 1.23 (6H, s, α-CH₃); 1.36 (2H, d, J=5Hz, --CH₂ --); 0.6-2.04ppm (8H, m, ring protons and OH).

Preparation of 2-methyl-(3,3,5,5-tetramethylcyclohexyl)-propyl-2-azide(10).

Boron trifluoride etherate (0.77 g, 0.69 ml, 5.44 mmol) was addeddropwise to a stirred solution of2-methyl-(3,3,5,5-tetramethylcyclohexyl)-propan-2-ol (9) (0.96 g, 4.53mmol) and trimethylsilyl azide (0.63 g, 0.72 ml, 5.44 mmol) in benzene(10 ml). After being stirred for 24 h at room temperature the mixturewas poured into water (20 ml). The organic phase was separated andwashed with saturated aqueous NaHCO₃ (10 ml) and saline (10 ml). Thesolution was dried over MgSO₄, filtered and concentrated. The crudeproduct was purified on silica gel column, eluting with hexane to give0.56 g (52%) of 10 as an oil.

¹ H NMR (CDCl₃, TMS) δ: 0.87 and 1.01 (total 12H, both s, cyclohexane3,5-CH₃); 1.27 (6H, s. α-CH₃); 1.36 (2H, d, J=5Hz, --CH₂ --); 0.6-1.85ppm (7H, m, ring protons).

Preparation of 2-(3,3,5,5-tetramethylcyclohexyl)-ethanol (11).

A solution of ethyl 3,3,5,5-tetramethylcyclohexylacetate 8 (1.8 g, 8.0mmol) in ether (30 ml) was added dropwise to a stirred suspension oflithium aluminum hydride (0.9 g, 24.0 mmol) in ether (30 ml), which wascooled in an ice bath. The reaction mixture was refluxed for 3 h, cooledand residual lithium aluminum hydride was destroyed with water. Theaqueous layer was separated and twice extracted with ether. The combinedether phases were washed with saline, dried over MgSO₄, filtered andevaporated. The crude product was purified by flash chromatography onsilica gel, eluting with hexane-ethyl acetate mixture (4:1) to give 1.2g (79%) of 11 as an oil.

¹ H NMR (CDCl₃, TMS) δ: 0.89 and 1.00 (total 12H, both s, cyclohexane3,5-CH₃); 1.44 (2H, q, J=7 Hz, 2-CH₂); 0.55-1.95 (8H, m, ring protonsand OH) and 3.70 ppm (2H, t, J=7 Hz, CH₂ O).

Preparation of 2-(3,3,5,5-tetramethylcyclohexyl)-ethylmethanesulfonate(12).

A solution of methanesulfonyl chloride (1.03 g, 0.7 ml, 9.0 mmol) in drybenzene (20 ml) was added to a stirred solution of2-(3,3,5,5-tetramethylcyclohexyl)-ethanol (11) (1.1 g, 6.0 mmol) andtriethylamine (1.2 g, 1.7 ml, 12 mmol) in benzene (40 ml), while coolingin an ice bath. The reaction mixture was stirred at room temperature for3 h, then filtered through a short silica gel column, eluting withbenzene. Evaporation of solvent gave 1.48 g (94%) of 12 as an oil.

¹ H NMR (CDCl₃, TMS) δ: 0.88 and 0.98 (total 12H, both s, cyclohexane3,5-CH₃); 1.62 (2H, q, J=7 Hz, 2-CH₂); 0.65-2.0 (7H, m, ring protons)3.0 (3H, s, CH₃ --SO₂) and 4.29 ppm (2H, t, J=7 Hz, CH₂ O).

Preparation of 2-(3,3,5,5-tetramethylcyclohexyl)-ethylazide (13).

The mixture of sodium azide (2.27 g, 34.2 mmol),2-(3,3,5,5-tetramethylcyclohexyl)-ethyl methanesulfonate-(12) (1.46 g,5.57 mmol) and dimethyl sulfoxide (20 ml) was stirred at roomTemperature for 48 h, diluted with water (50 ml) and extracted withether (3*30 ml). The organic phase was washed with saline (30 ml), driedover MgSO₄, filtered and evaporated. The crude product was purified byflash chromatography on silica gel, eluting with hexane to give 0.93 g(80%) of (13) as an oil.

¹ H NMR (CDCl₃, TMS) δ: 0.87 and 0.99 (total 12H, both s, cyclohexane3,5-CH₃); 1.47 (2H, q, J=7 Hz, 2-CH₂); 0.55-1.9 (7H, m, ring protons)and 3.31 ppm (2H, t, J=7 Hz, CH₂ N₃).

Preparation of N-formyl-1,3,3,5,5-pentamethylcyclohexanamine (14-1).

To a vigorously stirred solution of 1,3,3,5,5-pentamethylcyclohexanol(3-13) (2.7 g, 15.6 mmol) and trimethylsilyl cyanide (2.36 g, 23.8 mmol)in acetic acid (2.5 ml) under argon 98% sulfuric acid (4.66 g, 47.6mmol) was added, keeping temperature below -5° C. The mixture wasstirred at room temperature for 22 h, then it was poured onto ice (100g), neutralised with 50% NaOH solution to pH ˜7 and extracted with ether(3*30 ml). The combined ether phases were washed with saline (50 ml),then dried over MgSO₄ and evaporated. A slightly yellow crystallineresidue was treated with small amount of acetonitrile and filtered offto give 2.5 g (80%) of 14-1 as a white crystals, m.p. 104-106° C. ¹ HNMR (CDCl₃, TMS) δ: 0.91 and 0.93 (total 6H, both s, 3,5-CH_(3eq)); 1.08(2H, m, 2,6-CH_(eq)); 1.13 and 1.15 (total 6H, both s, 3,5-CH_(3ax));1.25 (2H, m, 4-CH₂); 1.32 and 1.38 (total 3H, both s, 1-CH₃); 1.70 and2.12 (total 2H, both d, 14.7 Hz, 2,6-CH_(ax)); 5.30 and 5.60 (total 1H,both br s, NH); 8.05 and 8.30 ppm (total 1H, both d, 2.0 and 12.7 Hz,resp., HCO).

Preparation of N-acetyl-1,3,3,5,5-pentamethylcyclohexanamine (14-2).

To a vigorously stirred solution of 1,3,3,5,5-pentamethylcyclohexanol(3-13) (3.0 g, 17.65 mmol) in acetonitrile (20 ml) fuming HNO₃ (6ml) wasadded dropwise, keeping temperature below 45° C. The resulting mixturewas stirred at -50° C. for 6 h, then it was cooled, poured into water(30 ml) ana neutralised with aqueous NH₃. Aqueous phase was extractedwith ether (3*30 ml). The combined ether phases were washed with saline(30 ml), then dried over MgSO₄, filtered and evaporated. The crudeproduct was crystallised from cold acetonitrile to give 223 g (60%) of14-2 as a white crystals, m.p. 110° C.

¹ H NMR (CDCl₃, TMS) δ: 0.90 and 1.12 (total 12H, both s, 3,5-CH₃); 1.33(3H, s, 1-CH₃); 1.88 (3H, s, CH₃ C═O); 0.75-2.25 (6H, m, ring protons)and 5.3 ppm (1H, br s, NH).

Preparation of N-methoxycarbonyl-N,1,3,3,5,5-hexamethylcyclohexanamine(15).

Methyl chloroformate (0.97 g, 0.8 ml, 10.3 mmol) was added in oneportion to a suspension of N,1,3,3,5,5-hexamethylcyclohexanaminehydrochloride (5-20) (1.13 g, 5.13 mmol) and Na₂ CO₃ (1.63 g, 15.4 mmol)in THF (30 ml). The resulting mixture was stirred at room temperaturefor 6 h, and then it was diluted with water (50 ml) and extracted withether (3*30ml). The combined organic phases were washed with 10% K₂ SO₄,saline, dried over MgSO₄, filtered and evaporated. The crude product waspurified by flash chromatography, eluting with hexane-ethyl acetatemixture (6:1) to give 0.90 g (78%) of (15) as an oil.

1H NMR (CDCl₃, TMS) δ: 0.93 and 1.07 (total 12H, both s, 3,5-CH₃); 1.23(3H, s, 1-CH₃); 1.0-1.4 (4H, m, 4-CH₂ and 2,6-CH_(eq)); 2.56 (2H, d,J=14 Hz, 2,6-CH_(ax)); 2.87 (3H, s, CH₃ N) and 3.64 ppm (3H, s, CH₃ 0).

Preparation of ethyl (3,3,5,5-tetramethylcyclohexylidene)cyanoacetate(16).

The mixture of 3,3,5,5-tetramethylcyclohexanone (2-13) (2.64g, 17 mmol),ethyl cyanoacetate (1.93, 17 mmol), acetic acid (0.2 ml) and ammoniumacetate (0.2 g) in benzene (6.4 ml) was refluxed with a Dean-Starkaparatus for 10 h. To this benzene (30 ml) and saline (30 ml) was added,organic layer separated, dried over Na₂ SO₄, filtered and evaporated.The crude product was purified by flash chromatography, eluting withhexane to give 2.0 g (50%) of (16) as an oil.

¹ H NMR (CDCl₃, TMS) δ: 1.01 (6H, s, 3,5-CH_(3eq)); 1.05 (6H, s, 3,5-CH₃ax); 1.34 (3H, t, J=7Hz, ethyl-CH₃); 1.42 (2H, s, 4-CH?); 2.46 and 2.79(total 4H, both s, 2,6-CH₂) and 4.29 ppm (2H, q, J=7 Hz, CH₂ O).

Preparation of ethyl (1,3,3,5,5-pentamethylcyclohexyl)cyanoacetate (17).

Anhydrous copper (I) chloride (0.8 g, 8 mmol) was added to a cooledsolution of alkylmagnesium iodide (prepared from magnesium (0.46 g, 19.2mmol) and iodomethane (2.84 g, 20 mmol)) in ether (12 ml). The mixturewas stirred in an inert atmosphere for 5 min and a solution of ethyl(3,3,5,5-tetramethylcyclohexylidene)cyanoacetate (16) (2 g, 8 mmol) inether (10 ml), was added dropwise keeping the temperature below -1 5 C.After the addition of ketone was completed, the reaction mixture wasstirred for 3 h and carefully neutralised with saturated aqueous NH₄ Clsolution. Traditional workup for Grignard reactions gave crude materialwhich was separated on a silica gel column, eluting with a petroleumether-ethyl acetate mixture (20:1) to give 1.0 g (47%) of 17 as an oil.

¹ H NMR (CDCl₃, TMS) δ: 0.98 (9H, s, 3,5-CH_(3eq) and 1-CH₃); 1.06 (6H,s, 3,5-CH_(3ax)); 1.31 (3H, t, J=7 Hz, ethyl-CH₃); 1.2-1.5 (6H, m, ringprotons); 3.41 (1H, s, α-CH) and 4.25 ppm (2H, q, J=7Hz, CH₂ O).

Preparation of 1-cyanomethyl-1,3,3,5,5-pentamethylcyclohexane (18).

The mixture of ethyl (1,3,3,5,5-pentamethylcyclohexyl)cyanoacetate (17)(1g, 3,7 mmol), LiCl (0.05 g) and water (0.15 ml) in DMSO (2.5ml) washeated at 150-160° C. for 4 h. Solution was poured into water (70 ml)and extracted with ether (4*20 ml). Ether was washed with saline (2*50ml), dried over Na₂ SO₄, filtered and evaporated. Crude product waspurified on silica gel column, eluting with a petroleum ether-ethylacetate mixture (20:1) to give 0.66 g (94%) of 18 as an oil.

¹ H NMR (CDCl₃, TMS) δ: 0.98 (9H, s, 3,5-CH_(3eq) and 1-CH₃); 1.02 (6H,s, 3,5-CH_(3ax)); 1.21 (3H, s, ring protons); 1.31 (3H, s, ring protons)and 2.31 ppm (2H, s, CH₂ CN). IR (neat) ν_(CN) =2242 cm⁻¹.

General procedure for preparation of alkylcyclohexanamine hydrochlorides5-1-5-25.

A solution of 4, 10 or 13-15, 18 in ether was added dropwise to astirred suspension of lithium aluminum hydride (4 equivalents) in ether,which was cooled in an ice bath. The reaction mixture was stirred atroom temperature in the case of 4, 10, 13 or refluxed in the case of 14,15, 18 till complete conversion of starting material (TLC control).Residual lithium aluminum hydride was destroyed with water, the aqueouslayer separated and twice extracted with ether. The combined etherphases were washed with saline, dried over NaOH, filtered andevaporated. The amine obtained was treated with HCl withoutcharacterization. The amine hydrochloride was prepared either by passingof HCl gas through the amine solution in hexane or by addition of a 1 NHCl solution in ether to the amine solution. In both cases the solventwas removed after HCl addition, the residue treated with hexane oracetonitrile and the crystalline product filtered off to give 5-1-5-25with excellent purity.

The physical properties and yields of compounds 5-1-5-25 are given inTable 4.

¹ H NMR spectral data of compounds 5-1-5-25 are given in Table 5.

Additional 1-aminoalkylcyclohexanes and their hydrochlorides areprepared in the same or a similar manner. The hydrochlorides can beconverted to the free base or other acid addition salts as disclosedunder "ACID ADDITION SALTS".

Preparation of 3,3,5,5-tetramethylcyclohexylmethylamine hydrochloride(5-26).

A solution of 1-nitromethyl-3,3,5,5-tetramethylcyclohexene (6) (1.1 g,5.63 mmol) in a mixture of ethanol (140 ml) and chloroform (2.8 ml) washydrogenated over 10% Pd/C (280 mg) at 5 atm for 20 h, filtered andevaporated. The crude product was treated with ether, filtered andwashed with ether to give 0.57 g (50%) of amine 5-26.

The physical properties and yield of compound 5-26 are given in Table 4.

¹ H NMR spectral data of compound 5-26 are given in Table 5.

Amine 5-27 was prepared according to the known procedure [16].

Amine 5-28 [17] was prepared according to the general procedure fromcorresponding azide [18]. All physical properties were in good agreementwith data described [17].

The purity of all compounds prepared was checked by GC (MN-OV-1,25m*0.53m, d_(f) =1.0 μm, 50-270° C. (10° C./min)).

ACID ADDITION SALTS

As acids suitable for the formation of acid addition salts according toconventional procedure, there may be mentioned from the mineral seriesthe following acids: hydrochloric, hydrobromic, methanesulfonic,isothionic, sulfuric, phosphoric, and sulfamic acids and, from theorganic series: acetic, propionic, maleic, fumaric, tartaric, citric,oxalic, and benzoic acids, to name a few. Preferred acids arehydrochloric, citric, and maleic. Other pharmaceutically-acceptable acidaddition salts may be prepared, if desired, and one acid addition saltmay be converted into another by neutralizing one salt, for example, thehydrochloride, resulting in the free base, and then reacidifying with adifferent selected mineral or organic acid, to prepare anotherpharmaceutically-acceptable acid addition salt, as is conventional inthe art.

                                      TABLE 1                                     __________________________________________________________________________    Cyclohexanones 2                                                                               Yield                                                        Compd.                                                                            R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                           R.sup.4                                                                          (%)                                                                              .sup.1 H--NMR (CDCl.sub.3, TMS) δ ppm               __________________________________________________________________________    2-10                                                                              Me    Me  Pr 81.5                                                                             0.86(3H, t, 6Hz); 0.98(3H, s); 1.01(3H, d, 5Hz),                              1.05-1.35(4H, m); 1.55-2.05(4H, m); 2.11(2H, s);                              2.34(1H, m)                                               2-11                                                                              Me Me     Et 54 0.88(3H, s); 0.90(3H, t, 7Hz); 1.06(3H, s);                                   1.15-1.45(2H, m); 2.13(2H, s); 1.45-2.45(5H, m)           2-12                                                                              Me Me     Pr 74 0.87(6H, m); 1.15(3H, s); 1.15-1.45(4H, m); 2.13(2H,                          s); 1.45-2.45(5H, m)                                      2-16                                                                              Me Me Et  Et 83.5                                                                             0.78(6H, t, 7Hz); 1.04(6H, s); 1.37(2H, q, 7Hz);                              1.52(2H, s); 2.16(4H, s)                                  2-17                                                                              Me Me Pr  Pr 79 0.87(6H, m); 1.03(6H, s); 1.25(8H, m); 1.53(2H, s);                           2.16(4H, s)                                               __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    1-Alkylcyclohexanols 3                                                                             Yield                                                    Compd.                                                                            R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                          (%) .sup.1 H--NMR(CDCl.sub.3, TMS)δ ppm            __________________________________________________________________________    3-2a          Et  Me 93  0.84(3H, t, 7Hz); 1.17(3H, s); 1.0-1.85(12H, m)      3-2b      Et      Me     0.87(3H, t. 7Hz); 1.21(3H, s); 1.0-1.85(12H, m)      3-3a          Pr  Me 93  0.86(3H, t, 7Hz); 1.18(3H, s); 1.0-1.9(14H, m)       3-3b      Pr      Me     0.86(3H, t, 7Hz); 1.19(3H, s); 1.0-1.85(14H, m)      3-6a      Me  Pr  Me 88  0.83(3H, s,); 0.86(3H, m); 1.19(3H, s);                                       1.0-1.85(13H, m)                                     3-6b      Pr  Me  Me     0.86(3H, t, 6.5Hz); 1.04(3H. s); 1.17(3H, s);                                 0.95-1.95(13H, m)                                    3-9 Me    Et  Me  Me 94  0.80(3H, s); 0.81(3H, t, 7Hz); 0.86(3H, d,                                    6.5Hz); 1.17(3H, s);0.9-2.0(10H,                                              m)                                                   3-10                                                                              Me    Pr  Me  Me 86  0.81(6H, m); 0.86(3H, d, 6.5Hz); 1.17(3H, s);                                 0.9-2.0(12H, m)                                      3-11                                                                              Me Me     Et  Me 84  0.87(6H, m); 1.08(3H, s); 1.18(3H, s);                                        0.95-1.95(10H, m)                                    3-12                                                                              Me Me     Pr  Me 88  0.88(6H, m); 1.09(3H, s); 1.18(3H, s);                                        0.9-1.95(12H, m)                                     3-15                                                                              Me Me Me  Me  Pr 85  0.89(9H, m); 1.21(6H, s); 0.95-1.7(11H, m)           3-16                                                                              Me Me Me(Et)                                                                            Et(Me)                                                                            Me 89  0.81(3H, t, 7Hz); 0.89, 1.17 and 1.21(total 12H,                              all s); 0.9-1.35(5H, m); 1.35-                                                2.0(4H, m)                                           3-17                                                                              Me Me Me(Pr)                                                                            Pr(Me)                                                                            Me 88  0.84(3H, m); 0.88 and 1.19(total 12H, both s);                                0.9-1.35(7H, m); 1.35-2.0(4H,                                                 m)                                                   3-18                                                                              Me Me Et  Et  Me 87  0.78(6H, t, 7Hz); 0.89(3H, s); 1.19(6H, s);                                   0.95-1.3(7H, m); 1.3-2.05(4H, m)                     3-19                                                                              Me Me Pr  Pr  Me 90  0.86(6H, t, 6.5); 0.88(3H, s); 1.18(6H, s);                                   0.9-1.3(11H, m); 1.3-2.05(4H, m)                     __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    1-Alkyl-1-azidocyclohexanes 4                                                 Com-                   Yield                                                  pound                                                                             R.sup.1                                                                           R.sup.2                                                                           R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                          (%) .sup.1 H--NMR(CDCl.sub.3, TMS)δ ppm          __________________________________________________________________________    4-1a            Me  Me 31  0.89(3H, d, 6.5Hz); 1.31(3H; s); 0.95-2.0(9H,                                 m)                                                 4-1b        Me      Me 6   0.92(3H, d, 6.5Hz); 1.28(3H, s); 1.0-2.0(9H,                                  m)                                                 4-2a            Et  Me 26  0.88(3H, t, 7Hz); 1.29(3H. s); 0.95-2.0(11H,                                  m)                                                 4-2b        Et      Me 4   0.88(3H. t, 6.5Hz); 1.27(3H. s); 1.0-2.0(11H,                                 m)                                                 4-3a            Pr  Me 24  0.88(3H, t, 6.5Hz); 1.29(3H, s); 1.0-2.0(13H,                                 m)                                                 4-3b        Pr      Me 11  0.88(3H, t, 6.5Hz); 1.27(3H, s); 1.0-2.0(13H,                                 m)                                                 4-4         Me  Me  Me 60  0.90(3H, s); 1.08(3H, s); 1.27(3H, s);                                        1.0-1.95(8H, m)                                    4-5         Me(Et)                                                                            Et(Me)                                                                            Me 60  0.82 and 1.04(total 3H, s); 0.82(3H, t, 7Hz);                                 1.28 and 1.29(total 3H, s);                                                   9.9-2.0(10H, m)                                    4-6         Me(Pr)                                                                            Pr(Me)                                                                            Me 66  0.85 and 1.07(total 3H, s); 0.87 and                                          0.90(total 3H, t, 6,5Hz); 1.29(3H, s);                                        1.0-1.95(12H, m)                                   4-7 Me(H)                                                                             H(Me)                                                                             H(Me)                                                                             Me(H)                                                                             Me 31  0.87(6H, d, 6Hz); 1.27 and 1.29(total 3H, s);                                 0.95-2.15(8H, m)                                   4-8a                                                                              Me      Me  Me  Me 42  0.86(3H, d, 6Hz); 0.89(3H, s); 1.09(3H, s);                                   1.27(3H, s); 9.95-1.9(7H, m)                       4-8b    Me  Me  Me  Me 12  0.92(3H, d, 6Hz); 0.94(3H, s); 0.97(3H, s);                                   1.36(3H, s); 0.95-2.0(7H, m)                       4-9a                                                                              Me      Et  Me  Me 47  0.81(6H, s and m); 0.86(3H, d, 6Hz); 1.27(3H,                                 s); 0.95-1.95(9H, m)                               4-9b    Me  Me  Et  Me 12  0.81(3H, t, 7Hz); 0.87(3H, s); 0.91(3H, d,                                    6Hz); 1.34(3H s) 1.95(9H m)                        4-10a                                                                             Me      Pr  Me  Me 44  0.81(3H, s); 0.84(3H, d, 6Hz); 0.87(3H, m);                                   1.27(3H, s); 1.0-2.0(11H, m)                       4-10b   Me  Me  Pr  Me 9   0.88(6H, s and m); 0.91(3H, d, 6Hz); 1.34(3H,                                 s); 1.0-1.95(11H, m)                               4-11a                                                                             Me  Me      Et  Me 45  0.91(3H, t, 7Hz); 0.92(3H, s); 1.12(3H, s);                                   1.31(3H, s), 1.0-1.9(9H, m)                        4-11b                                                                             Me  Me  Et      Me 12  0.92(3H, t, 7Hz); 0.97 and 0.99(total 6H, s);                                 1.37(3H, s), 1.0-1.9(9H, m)                        4-12a                                                                             Me  Me      Pr  Me 54  0.90(6H, s and m); 1.10(3H, s); 1.28(3H, s);                                  0.95-1.9(11H, m)                                   1-12b                                                                             Me  Me  Pr      Me 7   0.89(3H, t, 7Hz); 0.95(3H, s); 0.98(3H, s);                                   1.37(3H, s); 1.0-1.9(11H, m)                       4-13                                                                              Me  Me  Me  Me  Me 67  0.89(6H, s); 1.18(6H, s); 1.29(3H, s);                                        0.95-1.9(6H, m)                                    4-14                                                                              Me  Me  Me  Me  Et 39  0.89(6H, s); 0.96(3H, t, 7Hz); 1.19(6H, s);                                   1.0-1.9(8H, m)                                     4-15                                                                              Me  Me  Me  Me  Pr 65  0.89(6H, s); 0.93(3H, m); 1.16(6H, s);                                        1.0-1.8(10H, m)                                    4-16                                                                              Me  Me  Me(Et)                                                                            Et(Me)                                                                            Me 77  0.82(3H, m); 0.89, 1.14 and 1.18(total 9H, s);                                1.26 and 1.29(total 3H, s);                                                   0.95-1.9(8H, m)                                    4-17                                                                              Me  Me  Me(Pr)                                                                            Pr(Me)                                                                            Me 71  0.86; 0.88(total 3H, t, 6.5Hz); 0.90, 1.17;                                   1.19(total 9H, s); 1.28; 1.32(total 3H);                                      0.95-1.9(10H, m)                                   4-18                                                                              Me  Me  Et  Et  Me 66  0.78(6H, t, 7Hz); 0.90(3H, s); 1.18(3H, s);                                   1.31(3H, s); 0.95-1.95(10H, m)                     4-19                                                                              Me  Me  Pr  Pr  Me 61  0.89(9H, s and m); 1.17(3H, s); 1.27(3H, s);                                  0.95-1.95(14H, m)                                  __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Amino-cyclohexane derivatives 5                                                                      Elemental analysis                                                            Calculated(%)                                                                          Found(%)       Yield                          Mrz2/                                                                             Comp                                                                              Formula    M.W.                                                                              C  H  N  C  H  N  m.p. (° C.)                                                                  (%)                            __________________________________________________________________________    625 5-1a                                                                              C.sub.8 H.sub.17 N*HCl                                                                   163.72                                                                            58.7                                                                             10.5                                                                             8.6                                                                              58.7                                                                             10.5                                                                             8.6                                                                              >250  63                             631 5-1b                                                                              C.sub.8 H.sub.17 N*HCl                                                                   163.72                                                                            58.7                                                                             10.5                                                                             8.6                                                                              58.7                                                                             10.5                                                                             8.6                                                                              200-202                                                                             48                             629 5-2a                                                                              C.sub.9 H.sub.19 N*HCl                                                                   177.75                                                                            60.8                                                                             10.8                                                                             7.9                                                                              60.8                                                                             10.8                                                                             7.9                                                                              >250  66                             630 5-2b                                                                              C.sub.9 H.sub.19 N*HCl                                                                   177.75                                                                            60.8                                                                             10.8                                                                             7.9                                                                              60.8                                                                             10.8                                                                             7.9                                                                              179-181                                                                             43                             627 5-3a                                                                              C.sub.10 H.sub.21 N*HCl                                                                  191.78                                                                            62.6                                                                             11.1                                                                             7.3                                                                              62.6                                                                             11.1                                                                             7.3                                                                              >250  80                             626 5-3b                                                                              C.sub.10 H.sub.21 N*HCl                                                                  191.78                                                                            62.6                                                                             11.1                                                                             7.3                                                                              62.6                                                                             11.1                                                                             7.3                                                                              181-182                                                                             81                             621 5-4 C.sub.9 H.sub.19 N*HCl                                                                   177.75                                                                            60.8                                                                             10.8                                                                             7.9                                                                              60.8                                                                             10.8                                                                             7.9                                                                              230-231                                                                             73                             620 5-5 C.sub.10 H.sub.21 N*HCl                                                                  191.78                                                                            62.6                                                                             11.1                                                                             7.3                                                                              62.6                                                                             11.1                                                                             7.3                                                                              168-170                                                                             71                             617 5-6 C.sub.11 H.sub.23 N*HCl                                                                  205.81                                                                            64.2                                                                             11.3                                                                             6.8                                                                              64.2                                                                             11.3                                                                             6.8                                                                              106-108                                                                             68                             616 5-7 C.sub.9 H.sub.19 N*HCl                                                                   177.75                                                                            60.8                                                                             10.8                                                                             7.9                                                                              60.8                                                                             10.8                                                                             7.9                                                                              280-282                                                                             50                             607 5-8a                                                                              C.sub.10 H.sub.21 N*HCl                                                                  191.78                                                                            62.6                                                                             11.1                                                                             7.3                                                                              62.6                                                                             11.1                                                                             7.3                                                                              >240  74                             622 5-9a                                                                              C.sub.11 H.sub.23 N*HCl                                                                  205.81                                                                            64.2                                                                             11.3                                                                             6.8                                                                              64.2                                                                             11.3                                                                             6.8                                                                              250-253                                                                             68                             624 5-9b                                                                              C.sub.11 H.sub.23 N*HCl                                                                  205.81                                                                            64.2                                                                             11.3                                                                             6.8                                                                              64.2                                                                             11.3                                                                             6.8                                                                              228-231                                                                             60                             618 5-10a                                                                             C.sub.12 H.sub.25 N*HCl                                                                  219.84                                                                            65.6                                                                             11.9                                                                             6.4                                                                              65.6                                                                             11.5                                                                             6.4                                                                              167-168                                                                             57                             619 5-10b                                                                             C.sub.12 H.sub.25 N*HCl                                                                  219.84                                                                            65.6                                                                             11.9                                                                             6.4                                                                              65.6                                                                             11.5                                                                             6.4                                                                              237-238                                                                             36                             633 5-11a                                                                             C.sub.11 H.sub.23 N*HCl                                                                  205.81                                                                            64.2                                                                             11.3                                                                             6.8                                                                              64.2                                                                             11.3                                                                             6.8                                                                              255-257                                                                             69                             632 5-11b                                                                             C.sub.11 H.sub.23 N*HCl                                                                  205.81                                                                            64.2                                                                             11.3                                                                             6.8                                                                              64.2                                                                             11.3                                                                             6.8                                                                              216-218                                                                             44                             635 5-12a                                                                             C.sub.12 H.sub.25 N*HCl                                                                  219.84                                                                            65.6                                                                             11.9                                                                             6.4                                                                              65.6                                                                             11.5                                                                             6.4                                                                              218-221                                                                             83                             634 5-12b                                                                             C.sub.12 H.sub.25 N*HCl                                                                  219.84                                                                            65.6                                                                             11.9                                                                             6.4                                                                              65.6                                                                             11.5                                                                             6.4                                                                              200-203                                                                             44                             579 5-13                                                                              C.sub.11 H.sub.23 N*HCl                                                                  205.81                                                                            64.2                                                                             11.3                                                                             6.8                                                                              64.2                                                                             11.3                                                                             6.8                                                                              235-237                                                                             82                             600 5-14                                                                              C.sub.12 H.sub.25 N*HCl*H.sub.2 O                                                        237.86                                                                            60.6                                                                             10.6                                                                             5.9                                                                              60.6                                                                             10.6                                                                             5.9                                                                              215-218                                                                             74                             601 5-15                                                                              C.sub.13 H.sub.27 N*HCl                                                                  233.87                                                                            66.8                                                                             11.7                                                                             6.0                                                                              66.8                                                                             11.7                                                                             6.0                                                                              >280  88                             615 5-16                                                                              C.sub.12 H.sub.25 N*HCl                                                                  219.84                                                                            65.6                                                                             11.9                                                                             6.4                                                                              65.6                                                                             11.5                                                                             6.4                                                                              162-163                                                                             65                             614 5-17                                                                              C.sub.13 H.sub.27 N*HCl*0.5H.sub.2                                                       242.84                                                                            64.3                                                                             12.0                                                                             5.8                                                                              63.8                                                                             12.0                                                                             5.6                                                                              106-107                                                                             54                             623 5-18                                                                              C.sub.13 H.sub.27 N*HCl*H.sub.2 O                                                        251.89                                                                            62.0                                                                             10.8                                                                             5.6                                                                              62.0                                                                             10.8                                                                             5.6                                                                              99-102                                                                              78                             626 5-19                                                                              C.sub.15 H.sub.31 N*HCl                                                                  261.93                                                                            68.8                                                                             12.0                                                                             5.3                                                                              68.8                                                                             12.0                                                                             5.3                                                                              167-169                                                                             72                             640 5-20                                                                              C.sub.12 H.sub.25 N*HCl                                                                  219.84                                                                            65.6                                                                             11.9                                                                             6.4                                                                              65.6                                                                             11.7                                                                             6.3                                                                              249-251                                                                             86                             639 5-21                                                                              C.sub.13 H.sub.27 N*HCl                                                                  233.82                                                                            66.8                                                                             12.1                                                                             6.0                                                                              66.6                                                                             12.3                                                                             5.9                                                                              257-259                                                                             82                             642 5-22                                                                              C.sub.13 H.sub.27 N*HCl*H.sub.2 O                                                        251.82                                                                            62.0                                                                             12.0                                                                             5.6                                                                              62.0                                                                             12.0                                                                             5.5                                                                              >210  98                             645 5-23                                                                              C.sub.13 H.sub.29 N*HCl                                                                  247.85                                                                            67.8                                                                             12.2                                                                             5.7                                                                              67.6                                                                             12.3                                                                             5.6                                                                              205-207                                                                             89                             644 5-24                                                                              C.sub.12 H.sub.25 N*HCl                                                                  219.84                                                                            65.6                                                                             11.9                                                                             6.4                                                                              65.4                                                                             11.9                                                                             6.2                                                                              >250  83                             662 5-25                                                                              C.sub.13 H.sub.27 N*HCl*0.5H.sub.2 O                                                     242.84                                                                            64.3                                                                             12.0                                                                             5.8                                                                              64.9                                                                             11.9                                                                             5.7                                                                              >250  64                             580 5-26                                                                              C.sub.11 H.sub.23 N*HCl                                                                  205.81                                                                            64.2                                                                             11.3                                                                             6.8                                                                              64.1                                                                             11.4                                                                             6.9                                                                              >230  50                             557 5-27                                                                              C.sub.10 H.sub.21 N*HCl                                                                  191.75                                                                            62.6                                                                             11.6                                                                             7.3                                                                              62.3                                                                             11.6                                                                             7.2                                                                              >250(dec.)                                                                          70                             641 5-28                                                                              C7H15N*HCl 149.7                                                                             56.2                                                                             10.8                                                                             9.4                                                                              55.9                                                                             11.0                                                                             9.2                                                                              283-285                                                                             89                             __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    Spectral data of Amino-cyclohexane derivatives 5                              Compd.                                                                            .sup.1 H--NMR(CDCl.sub.3, TMS)δ ppm                                 __________________________________________________________________________    5-1a                                                                              0.89(3H, d, 6Hz); 0.9-1.4(3H, m); 1.44(3H, s); 1.5-2.3(6H, m);                8.3(3H, br s)                                                             5-1b                                                                              0.90(3H, d, 5Hz); 1.46(3H, s); 1.0-2.3(9H, m); 8.3(3H, br s)              5-2a                                                                              0.87(3H, t, 7Hz); 1.45(3H, s); 1.0-2.3(11H, m); 8.35(3H, br s)            5-2b                                                                              0.87(3H, t, 7Hz); 1.46(3H, s); 1.0-2.2(11H, m); 8.3(3H, br s)             5-3a                                                                              0.86(3H, t, 6.5Hz); 0.95-1.4(7H, m); 1.45(3H, s); 1.5-2.2(6H, m);             8.3(3H, br s)                                                             5-3b                                                                              0.85(3H, t, 7Hz); 1.47(3H, s); 0.95-2.2(3H, m); 8.3(3H, br s)             5-4 0.96(3H, s); 1.05(3H, s); 1.50(3H, s); 1.50(3H, s); 1.1-1.95(8H, m);          8.25(3H, br s)                                                            5-5 0.82(3H, t, 7Hz); 0.90 and 1.04(total 3H, both s); 1.48 and                   1.50(total 3H, both s); 1.1-2.0(10H, m); 8.25(3H, br s)                   5-6 0.88(3H, m); 0.94 and 1.07(total 3H, both s); 1.49 and 1.52(total 3H,         both s); 1.1-2.0(12H, m); 8.25(3H, br s)                                  5-7 0.90(6H, d, 6Hz); 1.44 and 1.50(total 3H, both s); 0.95-2.4(8H, m);           8.25(3H, br s)                                                            5-8a                                                                              0.90 and 0.91(total 6H, d, s); 1.23(3H, s); 1.44(3H, s); 0.95-2.3(7H,         m); 8.2(3H, br s)                                                         5-9a                                                                              0.83(s) and 0.87(m, total 9H); 1.47(3H, s); 1.0-2.2(9H, m); 8.15(3H,          br s)                                                                     5-9b                                                                              0.7-1.0(m) and 0.89(s, total 9H); 1.55(3H, s); 1.05-2.2(9H, m); (3H,          br s)                                                                     5-10a                                                                             0.7-0.95(m) and 0.86(s, total 9H); 1.51(3H, s); 0.95-2.3(11H, m);             8.2(3H, br s)                                                             5-10b                                                                             0.7-1.0(m) and 0.90(s, total 9H); 1.54(3H, s); 1.05-2.1(11H, m);              8.2(3H, br s)                                                             5-11a                                                                             0.8-1.0(m) and 0.91(s, total 6); 1.22(3H, s), 1.44(3H, s);                    1.0-2.3(9H, m); 8.2(3H, br s)                                             5-11b                                                                             0.88(m) and 0.96(s, total 9H); 1.50(3H, s); 1.0-2.15(9H, m); 8.2(3H,          br s)                                                                     5-12a                                                                             0.91(6H, m); 1.22(3H, s); 1.45(3H, s); 1.0-2.3(11H, m); 8.2(3H, br            s)                                                                        5-12b                                                                             0.89(m); 0.97(s, total 9H); 1.54(3H, s); 10-2.2(11H, m); 8.2(3H, br           s)                                                                        5-13                                                                              1.02 and 1.07(total 12H, s); 1.26(2H, m); 1.62(3H, s); 1.71(4H, m)        5-14                                                                              1.03 and 1.07(total 12H, s); 1.09(3H, t, 7Hz); 1.29(2H, s); 1.59 and          1.81(total 4H, d, 14Hz); 196(2H, q, 7Hz); 8.15(3H, br s)                  5-15                                                                              0.93(3H, t, 7Hz); 1.01 and 1.04(total 12H, s); 1.29(2H, s);                   135-2.0(4H, m); 1.70(4H, m); 8.2(3H, br s)                                5-16                                                                              0.83(3H, m); 1.00, 1.02 and 1.07(total 9H, s); 1.2-1.5(4H, m); 1.59           and 1.63(total 3H, both s); 1.70(4H, m); 8.25(3H, br s)                   5-17                                                                              0.87(3H, m); 1.0-1.1(9H, m); 1.1-1.4(6H, m); 1.60 and 1.64(total 3H,          both s); 1.70(4H, m); 8.25(3H, br s)                                      5-18                                                                              0.78(6H, t, 7Hz); 1.04(6H, s); 1.27(2H, m); 1.40(4H, m); 1.59(3H, s);         1.6-1.8(4H, m); 8.25(3H, br s)                                            5-19                                                                              0.87(6H, m); 1.04(6H, s); 1.1-1.5(10H, m); 1.60(3H, s); 1.5-1.95(4H,          m); 8.2(3H, br s)                                                         5-20                                                                              1.00 and 1.11(total 12H, s); 1.29(2H, m); 1.57(3H, s); 1.72(4H, dd,           14Hz); 2.56(3H, t, 6Hz); 9.2 ppm(2H, br s).                               5-21                                                                              0.98 and 1.11(total 12H, s); 1.29(2H, m); 1.58(3H, t, 7Hz); 1.61(3H,          s); 1.82(4H, m); 3.0(2H, m); 9.1 ppm(2H, br s)                            5-22                                                                              1.03 and 1.12(total 12H, s); 1.32(2H, m); 1.45(3H, s); 1.64 and               1.97(total 4H, d, 14Hz); 2.69(6H, d, 5Hz)                                 5-23                                                                              0.85(6H, s); 1.02(6H, s); 0.6-1.95(7H, m); 1.46(6H, s); 1.60(2H, d,           5Hz); 8.35(3H, br s)                                                      5-24                                                                              0.87(6H, s); 0.98(6H, s); 0.6-1.85(9H, m); 3.02(2H, m); 8.30(3H, br           s)                                                                        5-25                                                                              0.96(6H, s); 1.02(6H, s,); 1.07(3H, s); 1.18(6H, s); 1.73(2H, m);             3.03(2H, m); 8.28(3H, br s)                                               5-26                                                                              0.97(12H, br s); 1.0-2.2(7H, m); 2.80(2H, m); 8.35 ppm(3H, br s).         5-27                                                                              0.97(6H, s); 1.04(6H, s); 1.12(1H, d, 13.7Hz); 1.2-1.4(5H, m);                1.92(2H, d, 12.3Hz); 3.41(1H, m); 8.30(3H, br s)                          5-28                                                                              1.47(3H, s) 1.2-2.2(10H, m); 8.3(3H, br s)                                __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________    Basic Structure of the amino- and aminoalkylcyclohexanes.                      ##STR5##                                                                      ##STR6##                                                                     n + m = 0, 1, 2                                                               R.sup.1 - R.sup.9 = lower alkyl                                               Mrz 2/                                                                             Compd                                                                              R.sup.1                                                                            R.sup.2                                                                           R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                          R*                                            __________________________________________________________________________    625  5-1a H    H   H    Me   Me NH.sub.2                                      631  5-1b H    H   Me   H    Me NH.sub.2                                      629  5-2a H    H   H    Et   Me NH.sub.2                                      630  5-2b H    H   Et   H    Me NH.sub.2                                      627  5-3a H    H   H    Pr   Me NH.sub.2                                      628  5-3b H    H   Pr   H    Me NH.sub.2                                      621  5-4  H    H   Me   Me   Me NH.sub.2                                      620  5-5  H    H   Me (Et)                                                                            Et (Me)                                                                            Me NH.sub.2                                      617  5-6  H    H   Me (Pr)                                                                            Pr (Me)                                                                            Me NH.sub.2                                      616  5-7  Me (H)                                                                             H (Me)                                                                            H (Me)                                                                             Me (H)                                                                             Me NH.sub.2                                      643  5-8a Me   Me  Me   H    Me NH.sub.2                                      607  5-8a Me   Me  H    Me   Me NH.sub.2                                      622  5-9a Me   H   Et   Me   Me NH.sub.2                                      624  5-9b H    Me  Me   Et   Me NH.sub.2                                      618  5-10a                                                                              Me   H   Pr   Me   Me NH.sub.2                                      619  5-10b                                                                              H    Me  Me   Pr   Me NH.sub.2                                      633  5-11a                                                                              Me   Me  H    Et   Me NH.sub.2                                      632  5-11b                                                                              Me   Me  Et   H    Me NH.sub.2                                      635  5-12a                                                                              Me   Me  H    Pr   Me NH.sub.2                                      634  5-12b                                                                              Me   Me  Pr   H    Me NH.sub.2                                      579  5-13 Me   Me  Me   Me   Me NH.sub.2                                      600  5-14 Me   Me  Me   Me   Et NH.sub.2                                      601  5-15 Me   Me  Me   Me   Pr NH.sub.2                                      615  5-16 Me   Me  Me (Et)                                                                            Et (Me)                                                                            Me NH.sub.2                                      614  5-17 Me   Me  Me (Pr)                                                                            Pr (Me)                                                                            Me NH.sub.2                                      623  5-18 Me   Me  Et   Et   Me NH.sub.2                                      626  5-19 Me   Me  Pr   Pr   Me NH.sub.2                                      640  5-20 Me   Me  Me   Me   Me NHMe                                          639  5-21 Me   Me  Me   Me   Me NHEt                                          642  5-22 Me   Me  Me   Me   Me N(Me)2                                        645  5-23 Me   Me  Me   Me   H  CH.sub.2 CMe.sub.2 NH.sub.2                   644  5-24 Me   Me  Me   Me   H  CH.sub.2 CH.sub.2 NH.sub.2                    662  5-25 Me   Me  Me   Me   Me CH.sub.2 CH.sub.2 NH.sub.2                    580  5-26 Me   Me  Me   Me   H  CH.sub.2 NH.sub.2                             557  5-27 Me   Me  Me   Me   H  NH.sub.2                                      641  5-28 H    H   H    H    Me NH.sub.2                                      705  infra                                                                              Me   Me  Me   Me   Me N-pyrrolidine                                 __________________________________________________________________________

PHARMACEUTICAL COMPOSITIONS

The active ingredients of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages thereof, and insuch form may be employed as solids, such as coated or uncoated tabletsor filled capsules, or liquids, such as solutions, suspensions,emulsions, elixirs, or capsules filled with the same, all for oral use;in the form of suppositories or capsules for rectal administration or inthe form of sterile injectable solutions for parenteral (includingintravenous or subcutaneous) use. Such pharmaceutical compositions andunit dosage forms thereof may comprise conventional or new ingredientsin conventional or special proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Tablets containingtwenty (20) to one hundred (100) milligrams of active ingredient or,more broadly, ten (10) to two hundred fifty (250) milligrams per tablet,are accordingly suitable representative unit dosage forms.

METHOD OF TREATING

Due to their high degree of activity and their low toxicity, togetherpresenting a most favorable therapeutic index, the active principles ofthe invention may be administered to a subject, e.g., a living animal(including a human) body, in need thereof, for the treatment,alleviation, or amelioration, palliation, or elimination of anindication or condition which is susceptible thereto, orrepresentatively of an indication or condition set forth elsewhere inthis application, preferably concurrently, simultaneously, or togetherwith one or more pharmaceutically-acceptable excipients, carriers, ordiluents, especially and preferably in the form of a pharmaceuticalcomposition thereof, whether by oral, rectal, or parental (includingintravenous and subcutaneous) or in some cases even topical route, in aneffective amount. Suitable dosage ranges are 1-1000 milligrams daily,preferably 10-500 milligrams daily, and especially 50-500 milligramsdaily, depending as usual upon the exact mode of administration, form inwhich administered, the indication toward which the administration isdirected, the subject involved and the body weight of the subjectinvolved, and the preference and experience of the physician orveterinarian in charge.

EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS

With the aid of commonly used solvents, auxiliary agents and carriers,the reaction products can be processed into tablets, coated tablets,capsules, drip solutions, suppositories, injection and infusionpreparations, and the like and can be therapeutically applied by theoral, rectal, parenteral, and additional routes. Representativepharmaceutical compositions follow.

(a) Tablets suitable for oral administration which contain the activeingredient may be prepared by conventional tabletting techniques.

(b) For suppositories, any usual suppository base may be employed forincorporation thereinto by usual procedure of the active ingredient,such as a polyethyleneglycol which is a solid at normal room temperaturebut which melts at or about body temperature.

(c) For parental (including intravenous and subcutaneous) sterilesolutions, the active ingredient together with conventional ingredientsin usual amounts are employed, such as for example sodium chloride anddouble-distilled water q.s., according to conventional procedure, suchas filtration, aseptic filling into ampoules or IV-drip bottles, andautoclaving for sterility.

Other suitable pharmaceutical compositions will be immediately apparentto one skilled in the art.

The following examples are again given by way of illustration only andare not to be construed as limiting.

EXAMPLE 1 Tablet Formulation

A suitable formulation for a tablet containing 10 milligrams of activeingredient is as follows:

    ______________________________________                                                        Mg.                                                           ______________________________________                                               Active Ingredient                                                                        10                                                                 Lactose    63                                                                 Microcrystalline                                                                         21                                                                 Cellulose                                                                     Talcum      4                                                                 Magnesium stearate                                                                        1                                                                 Colloidal silicon                                                                         1                                                                 dioxide                                                                ______________________________________                                    

EXAMPLE 2 Tablet Formulation

Another suitable formulation for a tablet containing 100 mg is asfollows:

    ______________________________________                                                        Mg.                                                           ______________________________________                                        Active Ingredient 100                                                         Potato starch     20                                                          Polyvinylpyrrolidone                                                                            10                                                          Film coated and colored.                                                      The film coating material                                                     consists of:                                                                  Lactose           100                                                         Microcryst. Cellulose                                                                           80                                                          Gelatin           10                                                          Polyvinylpyrrolidone,                                                                           10                                                          crosslinked                                                                   Talcum            10                                                          Magnesium stearate                                                                               2                                                          Colloidal silicon dioxide                                                                        3                                                          Color pigments     5                                                          ______________________________________                                    

EXAMPLE 3

Capsule Formulation

A suitable formulation for a capsule containing 50 milligrams of activeingredient is as follows:

    ______________________________________                                                         Mg.                                                          ______________________________________                                        Active Ingredient  50                                                         Corn starch        20                                                         Dibasic calcium phosphate                                                                        50                                                         Talcum              2                                                         Colloidal silicon dioxide                                                                         2                                                         ______________________________________                                         filled in a gelatin capsule.                                             

EXAMPLE 4 Solution for injection

A suitable formulation for an injectable solution containing one percentof active ingredient is as follows:

    ______________________________________                                        Active Ingredient mg                                                                             12                                                         Sodium chloride mg 8                                                          Sterile water to make ml                                                                         1                                                          ______________________________________                                    

EXAMPLE 5 Liquid oral formulation

A suitable formulation for 1 liter of a liquid mixture containing 2milligrams of active ingredient in one milliliter of the mixture is asfollows:

    ______________________________________                                                        G.                                                            ______________________________________                                        Active Ingredient 2                                                           Saccharose        250                                                         Glucose           300                                                         Sorbitol          150                                                         Orange flavor     10                                                          Sunset yellow.                                                                Purified water to make                                                        a total of 1000 ml.                                                           ______________________________________                                    

EXAMPLE 6 Liquid oral formulation

Another suitable formulation for 1 liter of a liquid mixture containing20 milligrams of active ingredient in one milliliter of the mixture isas follows:

    ______________________________________                                                        G.                                                            ______________________________________                                        Active Ingredient 20                                                          Tragacanth        7                                                           Glycerol          50                                                          Saccharose        400                                                         Methylparaben     0.5                                                         Propylparaben     0.05                                                        Black currant-flavor                                                                            10                                                          Soluble Red color 0.02                                                        Purified water to make                                                        a total of 1000 ml.                                                           ______________________________________                                    

EXAMPLE 7 Liquid oral formulation

Another suitable formulation for 1 liter of a liquid mixture containing2 milligrams of active ingredient in one milliliter of the mixture is asfollows:

    ______________________________________                                                          G.                                                          ______________________________________                                        Active Ingredient   20                                                        Saccharose          400                                                       Bitter orange peel tincture                                                                       20                                                        Sweet orange peel tincture                                                                        15                                                        Purified water to make                                                        a total of 1000 ml.                                                           ______________________________________                                    

EXAMPLE 8 Aerosol formulation

180 g aerosol solution contain:

    ______________________________________                                                       G.                                                             ______________________________________                                               Active Ingredient                                                                       10                                                                  Oleic acid                                                                               5                                                                  Ethanol   81                                                                  Purified Water                                                                           9                                                                  Tetrafluoroethane                                                                       75                                                           ______________________________________                                    

15 ml of the solution are filled into aluminum aerosol cans, capped witha dosing valve, purged with 3.0 bar.

EXAMPLE 9 TDS formulation

100 g solution contain:

    ______________________________________                                                        G.                                                            ______________________________________                                        Active Ingredient 10                                                          Ethanol           57.5                                                        Propyleneglycol   7.5                                                         Dimethylsulfoxide 5.0                                                         Hydroxyethylcellulose                                                                           0.4                                                         Purified water    19.6                                                        ______________________________________                                    

1.8 ml of the solution are placed on a fleece covered by an adhesivebacking foil. The system is closed by a protective liner which will beremoved before use.

EXAMPLE 10 Nanoparticle formulation

10 g of polybutylcyanoacrylate nanoparticles contain:

    ______________________________________                                                        G.                                                            ______________________________________                                               Active Ingredient                                                                        1.0                                                                Poloxamer  0.1                                                                Butylcyanoacrylate                                                                       8.75                                                               Mannitol   0.1                                                                Sodiumchloride                                                                           0.05                                                        ______________________________________                                    

Polybutylcyanoacrylate nanoparticles are prepared by emulsionpolymersiation in a water/0.1 N HCl/ethanol mixture as polymerisationmedium. The nanoparticles in the suspension are finally lyophilizedunder vacuum.

PHARMACOLOGY--SUMMARY

The active principles of the present invention, and pharmaceuticalcompositions thereof and method of treating therewith, are characterizedby unique advantageous and unpredictable properties, rendering the"subject matter as a whole", as claimed herein, unobvious. The compoundsand pharmaceutical compositions thereof have exhibited, in standardaccepted reliable test procedures, the following valuable properties andcharacteristics:

They are systemically-active, uncompetitive NMDA receptor antagonistswith rapid blocking/unblocking kinetics and strong voltage dependencyand are accordingly of utility in the treatment, elimination,palliation, alleviation, and amelioration of responsive conditions, byapplication or administration to the living animal host for thetreatment of a wide range of CNS disorders which involve disturbances ofglutamatergic transmission.

PHARMACOLOGY

In vitro

Receptor Binding Studies

Male Sprague-Dawley rats (200-250 g) were decapitated and their brainswere removed rapidly. The cortex was dissected and homogenized in 20volumes of ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. Thehomogenate was centrifuged at 1000×g for 10 minutes. The pellet wasdiscarded and the supernatant centrifuged at 20,000×g for 20 minutes.The resulting pellet was re-suspended in 20 volumes of distilled waterand centrifuged for 20 minutes at 8000×g. Then the supernatant and thebuffy coat were centrifuged three times (48,000×g for 20 minutes) in thepresence of 50 mM Tris-HCl, pH 8.0. All centrifugation steps werecarried out at 4° C. After resuspension in 5 volumes of 50 mM Tris-HCl,pH 8.0 the membrane suspension was frozen rapidly at -80° C. On the dayof assay the membranes were thawed and washed four times by resuspensionin 50 mM Tris-HCl, pH 8.0 and centrifugation at 48,000×g for 20 minutes.The final pellet was suspended in assay buffer. The amount of protein inthe final membrane preparation was determined according to the method ofLowry with some modifications. The final protein concentration used forour studies was between 250-500 μg/ml.

Membranes were re-suspended and incubated in 50 mM Tris-HCl, pH 8.0.Incubations were started by adding [³ H]-(+)-MK-801 (23.9 Ci/mmol, 5nM)to vials with glycine (10 μM), glutamate (10 μM), and 0.1-0.25 mgprotein (total volume 0.5 ml) and various concentrations of the agentstested (10 concentrations in duplicates). The incubations were continuedat room temperature for 120 minutes, equilibrium always being achievedunder the conditions used. Non-specific binding was defined by theaddition of unlabeled MK-801 (10 μM). Incubations were terminated usinga Millipore filter system. The samples were rinsed three times with 2.5ml ice cold assay buffer over glass fiber filters obtained fromSchleicher & Schuell under a constant vacuum. Filtration was performedas rapidly as possible. Following separation and rinse, the filters wereplaced into scintillation liquid (5 ml; Ultima Gold) and radioactivityretained on the filters was determined with a conventional liquidscintillation counter (Hewlett Packard, Liquid Scintillation Analyser).

Patch Clamp

Hippocampi were obtained from rat embryos (E20 to E21) and were thentransferred to calcium and magnesium free Hank's buffered salt solution(Gibco) on ice. Cells were mechanically dissociated in 0.05% DNAase/0.3%ovomucoid (Sigma) following an 8 minute pre-incubation with 0.66%trypsin/0.1% DNAase (Sigma). The dissociated cells were then centrifugedat 18×g for 10 minutes, re-suspended in minimum essential medium (Gibco)and plated at a density of 150,000 cells cm⁻² onto poly-L-lysine(Sigma)-precoated plastic petri dishes (Falcon). The cells werenourished with NaHCO₃ /HEPES-buffered minimum essential mediumsupplemented with 5% fetal calf serum and 5% horse serum (Gibco) andincubated at 37° C. with 5% CO₂ at 95% humidity. The medium wasexchanged completely following inhibition of further glial mitosis withcytosine-β-D-arabinofuranoside (20 μM Sigma) after about 7 days invitro. Thereafter the medium was exchanged partially twice weekly.

Patch clamp recordings were made from these neurones with polished glasselectrodes (4-6 mΩ) in the whole cell mode at room temperature (20-22°C.) with the aid of an EPC-7 amplifier (List). Test substances wereapplied by switching channels of a custom-made fast superfusion systemwith a common outflow (10-20 ms exchange times). The contents of theintracellular solution were as follows (mM): CsCl (120), TEACI (20),EGTA (10), MgCl₂ (1),CaCl₂ -(0.2), glucose (10), ATP(2), cAMP (0.25); pHwas adjusted to 7.3 with CsOH or HCl. The extracellular solutions hadthe following basic composition (mM): NaCl (140), KCl (3), CaCl₂ (0.2),glucose (10), HEPES (10), sucrose (4.5), tetrodotoxin (TTX 3*10⁻⁴).Glycine (1μM) was present in all solutions: a concentration sufficientto cause around 80-85% activation of glycine, receptors. Only resultsfrom stable cells were accepted for inclusion in the final analysis,i.e., following recovery of responses to NMDA by at least 75% of theirdepression by the antagonists tested.

Excitotoxicity

Cortical neurones were obtained from cerebral cortices of 17/18 day oldfetal rats (Wistar), in general following the dissociation proceduredescribed by [23]. After short trypsinization and gentle triturationwith fire-polished Pasteur pipettes, the cell suspension was washed bycentrifugation. Cells were suspended in serum-free Neurobasal mediumwith B27 supplement (GIBCO) before plating onto poly-L-lysine (Sigma;0.2mg/ml, 20 h, 4° C.) and laminin (Sigma; 2 μg/ml, 1h, 37° C.)-coated96-well plates (Falcon, Primaria) at a density of 5×10⁴ cells/well.Cortical neurones were maintained at 37° C. in humidified 10% CO₂ /90%air. One day after plating, 5 μM cytosine-β-D-arabinofuranoside (Sigma)was added to each well for inhibition of glial cell proliferation. Themedium was changed first after 4 days in vitro and then every 4 days byreplacing 2/3 of the medium with astrocyte-conditioned medium. Corticalneurones between day 12 and 14 in culture were used for the experiments.

New-born rat astrocytes were isolated non-enzymatically according to themethod of [24]. Briefly, both hemispheres were dissected from 2-day-oldrats, passed through an 80 μm gauze, and triturated with Pasteurpipettes. Cell suspension was made in Dulbecco's modified essentialmedium (DMEM, Gibco) supplemented with 10% fetal calf serum (FCS,Hyclone), 2mM glutamine (Gibco) and 50 μg/ml gentamycin and transferredinto untreated, plastic culture flasks (Corning; 75 cm³). Two days afterplating the flasks were shaken for 10 minutes on a rotary platform (150U/min) to remove microglial cells. The cultures were grown to confluencywithin 14 days, and the culture medium was changed twice weekly.Thereafter, the glial monolayers were extensively washed with serum-freeNeurobasal medium (Gibco) to remove the serum. Flasks were then shakenseveral times to remove oligodendrocytes and neurones. To obtainconditioned medium from primary astrocytes, the cultures were incubatedwith fresh Neurobasal medium supplemented with B27 and glutamine. Every2-3 days the conditioned medium was collected and replaced by freshmedium up to 4 times.

Exposure to EAA was performed in serum-free Neurobasal medium containing100 μM glutamate and the drug to be tested. After 20 h of incubation,the cytotoxic effect was morphologically examined under a phase contrastmicroscope and biochemically quantified by measuring cell viability withthe MTT test (Promega). This calorimetric assay measures the reductionof a tetrazolium component (MTT) into an insoluble formazan product bythe mitochondria of living cells. After incubation of the corticalneurones with the dye solution for approximately 1-4 hours, asolubilization solution was added to lyse the cells and solubilize thecolored product (incubation overnight at 37° C., 10% CO₂, 90% RH). Thesesamples were then read using an Elisa plate reader (Thermomax, MWGBiotech) at a wavelength of 570 nm. The amount of color produced wasdirectly proportional to the number of viable cells.

In vivo

Anticonvulsive activity

NMR female mice (18-28 g) housed 5 per cage were used for the maximalelectroshock (MES) and motor impairment tests. All animals were keptwith water and food ad libitum under a 12 hour light-dark cycle (lighton at 6 a.m.) and at a controlled temperature (20±0.5° C.). Allexperiments were performed between 10 a.m. and 5 p.m. Tested agents wereinjected 30 min. i.p. before the induction of convulsions if not statedotherwise (see below). All compounds were dissolved in 0.9% saline.

The MES test was performed together with tests for myorelaxant action(traction reflex) and motor coordination (rotarod). For the tractionreflex test mice were placed with their forepaws on a horizontal rod andwere required to place all 4 paws on the wire within 10 seconds. To testataxia (motor coordination) mice were placed on rotarod (5 rpm) and wererequired to remain on the rod for 1 minute. Only mice not achieving thecriteria in all three repetitions of each test were considered toexhibit myorelaxation or ataxia respectively. These tests were followedby MES (100 Hz, 0.5 second shock duration, 50 mA shock intensity, 0.9 msimpulse duration, Ugo Basile) applied through corneal electrodes. Thepresence of tonic convulsions was scored (tonic extension of hind pawswith minimum angle to the body of 90°). The aim was to obtain ED₅₀ s forall parameters scored (anticonvulsive activity and motor side effects)with use of the Litchfield Wilcoxon test for quantal dose responses.Division of the ED₅₀ for side effects (ataxia or myorelaxation) by theED₅₀ for antagonism of electroshock convulsions was used as atherapeutic index (TI).

Statistical analysis

IC₅₀ s in patch clamp, excitotoxicity, and binding studies werecalculated according to the four parameter alogistic equation using theGrafit computer program (Erithacus Software, England). Ki value forbinding studies were then determined according to Cheng and Prusoff.Binding values presented are means ±SEM of 3-5 determinations (eachperformed in duplicate).

4-7 doses of antagonists were tested in each of the in vivo tests (5-8animals per dose) to allow calculation of graded ED₅₀ s according toprobit analysis (Litchfield and Wilcoxon) with correction for 0% to 100%effects. ED₅₀ s are presented with 95% confidence limits (Cl). Pearsonproduct moment correlation analysis (Sigma Stat, Jandel Scientific) wasused to compare in vitro potencies and in vivo anticonvulsant activity.

RESULTS

Binding

All cyclohexanes displaced [³ H]-(+)-MK-801 binding to rat corticalmembranes with IC₅₀ s of between 4 and 150 μM whilst Ki values asassessed with the Cheng-Prussoff equation were 2 fold lower (see Table7).

Patch Clamp

Steady-state inward current responses of cultured hippocampal neuronesto NMDA (200 μM with glycine 1 μM at -70 mV) were antagonized by thetested cyclohexanes with IC₅₀ s of 1.3-99 μM (Table 7). Peak andsteady-state currents were affected to a similar degree making itunlikely that their effects were mediated at the glycine_(B) site.Strong support for the uncompetitive nature of this antagonism wasprovided by the clear use- and voltage-dependency of their blockade. Theweaker antagonists showed faster kinetics and strongervoltage-dependency.

Excitotoxicity

Low μM concentrations of most cyclohexanes were effectiveneuroprotectants in vitro, with Mrz 2/579 seeming to be most potent inthis regard (see Table 7). With most compounds full protection wasobtained with 20 μM.

In vivo

Anticonvulsive activity

All cyclohexane derivatives inhibited MES-induced convulsions in micewith ED₅₀ s ranging from 3.6 to 50 mg/kg i.p. (Table 7). Selectedcompounds were also tested against PTZ- and NMDA-induced convulsions(see [20,21] for methods) and showed comparable potency to the MES test(e.g., Mrz 2/579 had ED₅₀ s in the PTZ- and NMDA tests of 5.5 and 3.7mg/kg respectively). Their anticonvulsive potency was increasedfollowing i.v. administration (e.g., Mrz 2/579 ED₅₀ =2.5 mg/kg). Mrz2/579 was also active following s.c. and somewhat less potent followingp.o. administration (ED₅₀ s of 4.6 and 13.7 mg/kg respectively). Atdoses within the anticonvulsive range, myorelaxation (traction test) andataxia (rotarod test) were observed with some cyclohexanes. For themajority of them, no acute lethality was seen at up to 50 mg/kg.

Correlation Analysis

There was a very good cross correlation between all three in vitroassays (all corr. coeffs.>0.70, p<0.001). There was also a goodcorrelation between potencies in antagonizing NMDA-induced inwardcurrents and protection against NMDA-induced toxicity in vitro withanticonvulsive activity in vivo (corr. coeffs.>0.56, p<0.01).

                                      TABLE 7                                     __________________________________________________________________________           [.sup.3 H]MK-801                                                                          Patch Clamp                                                                              Glut. Tox.                                                                             MES ED.sub.50                          Mrz2/  IC.sub.50 (μM)(μM)                                                              SEM IC.sub.50 (μM)                                                                    SEM IC.sub.50 (μM)                                                                   SD mg/kg C.I.                             __________________________________________________________________________    557    17.6    0.9 18.5   2.7 6.7   2.0                                                                              43.9  35.6-54.1                        579    1.9     0.1 1.3    0.02                                                                              2.2   0.0                                                                              3.6   2.2-6.1                          580    15.9    0.8 12.9   0.4 5.6   0.6                                                                              27.3  12.8-64                          600    24      0.1 3.7    0.2 2.1   0.2                                                                              22.6  43.0-197                         601    7.4     0.7 10.5   0.8 3.5   0.3                                                                              15.6  10.4-23.4                        607    8.2     0.3 13.6   1.5 10.1  2.2                                                                              22.9  18.3-28.7                        614    13.6    1.3 13.9   1.9 >10      23.5  15.7-34.9                        615    2.5     0.1 2.9    0.1 2.3   0.1                                                                              6.1   3.4-10.7                         616    150     0.4 34.2   4.6 9.1   2.1                                                                              24.0  15.6-36.8                        617    51.8    3.9 57.4   7.3 >70      54.9  42.9-70.4                        618    32.7    2.4 43.7   9.4 17.6  2.9                                                                              24.0  9.6-59.5                         619    72.1    6.7 60.8   5.4 30.9  2.9                                                                              44.6  32.0-62.3                        620    32.2    2.1 99.0   10.4                                                                              38.4  1.6                                                                              41.3  32.9-51.7                        621    36.7    4.4 92.4   19.0                                                                              >100     36.9  22.6-60.3                        622    150     0.6 64.8   11.7                                                                              19.3  8.1                                                                              21.0  16.1-27.5                        623    3.3     0.2 3.7    0.7 4.5   0.6                                                                              13.1  9.9-17.2                         624    15.4    1.2 31.0   3.6 2.7   0.6                                                                              47.2  41.8-53.2                        625    46.8    8.1 244.9  40.1                                                                              39.4  6.3                                                                              129.8 42.5-395.6                       626    11.6    1.5 9.6    2.0 19.0  3.3                                                                              41.2  29.9-56.7                        627    70.3    3.3 209.7  1.0 26.6  5.7                                                                              43.9  30.3-63.7                        628    35.6    4.4 125.5  0.8 27.3  4.5                                                                              73.2  33.6-159.4                       629    39.4    2.4 218.6  1.6 >300     58.5  38.3-89.2                        630    443     3.8 >100       >100     >30                                    631    69.7    8.6 >100       >100     30.00                                  632    2.0     0.2 6.4    0.6 10.9  0.4                                                                              11.04 7.7-15.8                         633    6.6     0.5 13.9   3.2 5.4   0.9                                                                              8.78  3.6-21.4                         634    15.5    1.0 10.8   2.6 19.0  3.5                                                                              >30                                    635    7.8     0.4 21.0   4.6 8.2   1.4                                                                              31.59 21.3-46.6                        639    3.3     0.3 7.4    1.0 5.7   0.4                                                                              5.5   3.6-9.0                          640    3.7     0.6 14.6   1.2 8.3   0.4                                                                              8.2   5.7-11.8                         641    184.5   26.7                                                                              >100       >100     >50                                    642    10.2    1.6 42.5   6.5 29.3  3.3                                                                              8.04  5.1-12.7                         643    3.6     0.5 13.5   1.7 12.0  0.9                                                                              16.65 10.8-32.2                        644    3.8     3.7 4.1    1.8 4.3   0.4                                                                              52.98 27.8-100.8                       645    85.1    30.6                                                                              20.4   3.6 >100     65.61 43.8-98.2                        Memantine                                                                            0.7     0.11                                                                              2.3    0.3 1.3   0.7                                                                              6.9   5.4-8.8                          Amantadine                                                                           20.4    5.4 71.0   11.1                                                                              20.7  0.7                                                                              184.0 122-279                          MK-801 0.0026  0.0002                                                                            0.14   0.10                                                                              0.012 0.002                                                                            0.16  0.13-0.21                        __________________________________________________________________________

Effects of cyclohexane derivatives and standard uncompetitive NMDAreceptor antagonists on [³ H]-(+)-MK-801 binding, NMDA induced currentsin patch clamp experiments, glutamate toxicity in cultured corticalneurones and MES-convulsions in vivo. Binding Ki values are means TSEMof 3-5 experiments. IC₅₀ s (+SEM) in patch clamp and glutamate toxicityexperiments were determined from data from at least 3 concentrationsproducing between 15 and 85% inhibition and at least 5 cells perconcentration. For MES-induced convulsions, values are ED₅₀ s in mg/kg(95% confidence limits are shown in parentheses).

In addition, due at least in part to their amine substituent, thecompounds of the present invention are =also effective in non-NMDAindications, exhibiting immuno-modulatory activity, antimalaria potency,anti-Borna virus activity, and anti-Hepatitis C activity.

ADDITIONAL EXAMPLES AND PHARMACOLOGICAL UPDATES

Further 1-aminoalkylcyclohexane compounds, wherein the 1-amino group iscyclic, that is, wherein R⁸ and R⁹ together represent lower-alkylene--(CH2)x-- wherein x is 2 to 5, inclusive, thereby presenting the1-amino group --NR⁸ R⁹ in the form of a cyclic amine, are prepared inthe following manner:

Preparation of N-(3-Cyanopropyl)-1,3,3,5,5-Pentamethylcyclohexylamine(2)

A mixture of 1,3,3,5,5-pentamethylcyclohexylamine hydrochloride (1)(2-06 g, 10 mmol) 4-bromobutyronitrile (1.55 g. 10.5 mmol) and sodiumcarbonate (3.18 g, 30 mmol) in tetrahydrofuran (50 ml) was refluxed for85 h, the poured into water (100 ml) and extracted with ether (3*30 ml).The combined organic phases were washed with brine (20 ml) and driedover K₂ CO₃. The solution was filtered and evaporated and the crudeproduct was purified by chromatography on silica gel, eluting withhexane-ether (10:1), (6:1), (4:1) to give product 2 (1.86 g, 86%) as ancolorless oil.

PMR spectrum: (CDCl₃, TMS) δ: 0.87 (6H, s, c-Hex 3,5-CH₃); 1.06 (3H, s,c-Hex 1-CH₃); 1.18 (6H, s, 3,5-H₃); 0.9-1.6 (7H, m, c-Hex ring protonsand NH); 1.75 (2H, m, --CH₂ --); 2.43 (2H, t, J=7 Hz, CH₂ N) and 2.66ppm. (2H, t, J=7 Hz, CH₂ CN).

Preparation of MRZ 2/705. namely: N-(1,3,3,5,5-Pentamethylcyclohexyl)pyrrolidine hydrochloride (3)

N-(3-Cyanopropyl)-1,3,3,5,5-pentamethylcyclohexylamine (2) (1.2 g, 5.1mmol) in ethanol (120 ml) and conc. HCl (4 ml) was hydrogenated over 10%Pd/C (250 mg) at 7 bar for 40 h (after 24 h additional portion ofcatalyst (260 mg) was added). The catalyst was removed by filtrationthrough celite pad and solvent evaporated. The residue was treated withacetonitrile, the solids filtered off and the filtrate evaporated. Thecrude product vas crystallized from ether to giveN-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine hydrochloride (3) (0.67g, 49%) with m.p. 156-158° C.

PMR spectrum: (DMSO-d₆, TMS) δ: 0.97 (6H, s, 3,5-CH₃); 1.11 (6H, s,3,5-CH₃); 0.8-1.4 (2H, cyclohexane 4-CH₂) 1.41 (3H, s, 1-CH₃); 1.69 (4H,m, cyclohexane 2,6-CH₂); 1.84 (4H, m, pyrrolidine 3,4-CH₂) 3.20 (4H, m,pyrrolidine 2,5-CH₂); 10.9 ppm (1H, br s, NH⁺). Elemental analysis: C₁₅H₂₉ N*HCl*0.5H₂ O: Found (%) C, 67.7; H, 11.5; N, 5.5. Calculated (%) C,67.0; H, 11.6; N, 5.2.

Additional 1-cyclic amino compounds are prepared in the same mannerstarting from the selected alkyl-substituted cyclohexylamine, usually inthe form of an acid addition salt such as the hydrochloride, and theselected w-bromoalkylnitrile, such as 4-bromobutyronitrile,3-bromopropionitrile, 2-bromoacetonitrile, and 5-bromovaleronitrile, inthe manner of the preceding preparation, first to produce the selectedN-ω-cyanoalkyl-alkylcyclohexylamine compound and then to cyclize theN-ω-cyanoalkyl-alkylcyclohexylamine compound into the resultingN-(alkylcyclohexyl) cyclic amine compound, namely, the pyrrolidine,piperidine, or other cyclic amine compound, wherein the nitrogen atomand R⁸ and R⁹ together form the cyclic amine moiety, R⁸ and R⁹ togetherrepresenting a lower-alkylene chain of the formula --(CH₂)_(x) --wherein x is 2 to 5, inclusive.

Thus N-(1,3,3,5,5-pentamethylcyclohexyl) piperidine hydrochloride orother acid addition salt and numerous other lower-alkyl substitutedcyclohexanes having a 1-pyrrolidino or 1-piperidino group or other1-cyclic amino group are prepared according to the invention, dependingupon the ω-bromoalkylnitrile and the alkyl-substituted cyclohexylaminestarting materials selected for the reaction.

UPDATED PHARMACOLOGICAL TABLES

The following Tables 8 and 9 present updated pharmacological resultswith various of the compounds of the present invention. The Tables showthe following:

                                      TABLE 8                                     __________________________________________________________________________           MES ED.sub.50         Min I.cthality mg/kg                             MRZ2/  mg/kg i.p.  TI Tract                                                                           TI Rot.                                                                            i.p.                                             __________________________________________________________________________    557    43.9  (35.6-54.1)                                                                         1.0  1.4  >70                                              579    3.6   (2.2-6.1)                                                                           2.9  5.0  108                                              580    27.3  (12.8-64)                                                                           1.6  1.3  50                                               600    22.6  (10.4-23.2)                                                                         0.6  0.9  50                                               601    15.6  (10.4-23.4)                                                                         1.5  1.5  50                                               607    22.9  (18.3-28.7)                                                                         1.3  1.7  50                                               614    23.5  (15.7-34.9)                                                                         1.9  1.6  >50                                              615    6.1   (3.4-10.7)                                                                          2.5  3.2  50                                               616    24.0  (15.6-36.8)                                                                         1.0  1.4  >50                                              617    54.9  (42.9-70.4)                                                                         1.1  1.1  >50                                              618    24.0  (9.6-59.5)                                                                          1.2  1.1  >50                                              619    44.6  (32.0-62.3)                                                                         1.0  1.0  >50                                              620    41.3  (32.9-51.7)                                                                         1.6  1.1  >50                                              621    36.9  (22.6-60.3)                                                                         1.8  1.5  >60                                              622    21.0  (16.1-27.5)                                                                         1.1  1.7  50                                               623    13.1  (9.9-17.2)                                                                          1.4  1.8  >30                                              624    47.2  (41.3-53.2)                                                                         0.9  1.0  100                                              625    129.8 (42.5-395.6)                                                                        0.5  1.2  >70                                              626    41.2  (29.9-56.7)                                                                         1.1  1.0  >50                                              627    43.9  (30.3-63.7)                                                                         0.8  1.0  60                                               628    73.2  (33.6-159.4)                                                                        0.8  1.6  >60                                              629    58.5  (38.3-89.2)                                                                         0.9  0.9  100                                              630    >30         nc   nc   >30                                              631    30          nc   nc   >30                                              632    11.04 (7.7-15.8)                                                                          2.7  3.4  >30                                              633    8.78  (3.6-21.4)                                                                          2.4  3.0  108                                              634    >30         nc   nc   >30                                              635    31.59 (21.3-46.8)                                                                         1.3  1.4  >50                                              639    5.87  (3.8-9.0)                                                                           2.6  4.4  30                                               640    8.18  (5.7-11.8)                                                                          2.3  3.3  108                                              641    >50         nc   nc   >50                                              642    8.04  (5.1-12.7)                                                                          4.1  5.3                                                   643    18.65 (10.8-32.2)                                                                         1.3  2.4  >50                                              644    52.98 (27.8-100.8)                                                                        0.5  0.6  >35                                              645    65.61 (43.8-98.2)                                                                         0.6  0.6                                                   662    30.47 (18.0-51.6)                                                                         1.0  1.2  >40                                              680    34.5  (27.1-44.0)                                                                         0.7  1.1  >50                                              681    27.9  (18.2-42.6)                                                                         2.1  5.3  >50                                              682    7.6   (4.5-13.0)                                                                          2.7  3.6  >50                                              683    12.2  (6.3-23.5)                                                                          2.7  3.5  >50                                              705    9.55  (4.3-21.1)                                                                          3.9  5.4  >50                                              Memantine                                                                            6.9   (5.4-8.8)                                                                           2.9  2.5  >108                                             Amantadine                                                                           184.0 (122-279)                                                                           0.5  0.6  >324                                             MK-801 0.16  (0.13-0.21)                                                                         1.0  1.2  >108                                             __________________________________________________________________________

Table 8

Effect of the present amino-alkyl-cyclohexane derivatives and standarduncompetitive NMDA receptor antagonists on convulsions induced bymaximal electroshock (MES). Values are ED₅₀ S in mg/kg (95% confidencelimits are shown in parentheses). The therapeutic index (TI) was alsocalculated as the ED₅₀ for inhibition of traction reflex (Tract.)impairment or rotarod failure (Rot.) divided by the ED₅₀ for MES-inducedseizure-induced convulsions. Most of the amino-alkyl-cyclohexanederivatives showed no acute toxicity, i.e., minimal lethal doses wereabove 50 mg/kg.

                                      TABLE 9                                     __________________________________________________________________________           MK-801 Ki   Patch Clamp                                                                              Glut Tox IC.sub.50                              MRZ    (μM)                                                                             SEM   IC.sub.50 (μM)                                                                    SEM (μM) SEM                                     __________________________________________________________________________    557    19.92 2.98  18.50  2.70                                                                              6.70    2.00                                    579    1.47  0.13  1.29   0.20                                                                              2.16    0.03                                    580    17.84 1.33  12.90  0.40                                                                              5.60    0.80                                    600    2.28  0.21  3.49   0.47                                                                              2.10    0.20                                    601    8.09  0.43  10.00  0.20                                                                              3.50    0.30                                    607    7.74  0.29  13.90  1.50                                                                              10.10   2.20                                    614    13.59 0.12  13.90  1.90                                                                              1.26    0.19                                    615    2.42  0.11  2.90   0.40                                                                              2.29    0.15                                    616    10.42 2.00  33.20  2.50                                                                              9.10    2.10                                    617    38.03 8.56  63.90  7.70                                                                              >70     nc                                      618    24.02 5.33  57.50  11.90                                                                             17.60   2.90                                    619    57.76 8.96  60.90  5.40                                                                              30.90   2.90                                    620    25.48 4.34  99.00  10.40                                                                             38.40   1.60                                    621    32.20 8.30  92.40  19.50                                                                             >100    nc                                      622    13.32 3.29  58.20  8.50                                                                              19.30   8.10                                    623    3.16  0.31  3.70   0.70                                                                              4.50    0.60                                    624    15.14 2.36  31.00  3.60                                                                              2.70    0.60                                    625    52.61 3.69  244.90 40.50                                                                             39.40   6.30                                    626    16.48 4.21  9.60   2.00                                                                              19.00   3.33                                    627    70.95 11.22 150.00 27.00                                                                             26.60   5.70                                    628    49.18 4.35  125.50 22.60                                                                             27.30   4.50                                    629    49.28 2.60  218.60 39.30                                                                             >300    nc                                      630    49.10 5.09  100.00 11.00                                                                             >100    nc                                      631    65.29 13.64 >100   nc  >100    nc                                      632    2.88  0.28  6.40   0.60                                                                              11.20   0.27                                    633    5.18  1.11  13.90  3.20                                                                              6.10    1.84                                    634    13.40 4.25  10.80  2.70                                                                              19.00   3.50                                    635    15.01 1.85  21.00  4.70                                                                              8.18    1.43                                    639    4.17  0.32  7.40   1.00                                                                              6.33    0.16                                    640    4.83  0.56  14.60  1.90                                                                              8.35    0.51                                    641    143.33                                                                              36.76 >100   nc  >100    nc                                      642    12.72 3.15  42.50  6.50                                                                              29.30   3.34                                    643    4.66  0.12  13.50  l.70                                                                              12.00   0.87                                    644    4.84  0.35  4.10   1.80                                                                              4.30    0.42                                    645    60.17 8.38  20.40  3.60                                                                              >100    nc                                      662    3.44  0.77  1.50   0.05                                                                              0.53    0.04                                    680    29.96 8.96  43.00  5.5 35.6    4.1                                     681    19.21 4.81  30.00  3.4 26.9    3.1                                     682    1.99  0.19  3.90   0.56                                                                              3.11    0.20                                    683    4.44        4.30   0.70                                                                              5.08    0.34                                    705    7.14  1.7   25.40  4.1 nt      nt                                      Amantadine                                                                           25.87 2.99  80.80  10.40                                                                             36.91   5.52                                    Memantine                                                                            2.45  0.91  2.87   0.44                                                                              1.40    0.10                                    MK-801 6.56 * 10.sup.-3                                                                    0.33 * 10.sup.-3                                                                    0.1400 0.1000                                                                            0.0130  0.0020                                  __________________________________________________________________________

Table 9

Effect of amino-alkyl-cyclohexane derivatives and standard uncompetitiveNMDA receptor antagonists on [³ H]-(+)-MK-801 binding, NMDA-inducedcurrents in patch clamp experiments, and glutamate toxicity in culturedcortical neurones. Binding Ki values are means ±SEM of 3-5 experimentsand were determined according to the Cheng-Prusoff relationship with aKd for MK-801 of 4.6 nM. IC₅₀ s (±SEM) in patch clamp and glutamatetoxicity experiments were determined from data from at least 3concentrations producing between 15 and 85% inhibition and at least 5cells/well per concentration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and FIG. 1B show values obtained for these effects using MRZ2/705.

FIG. 2 shows the values obtained for various compounds of the inventionand reference standards in the specific [³ H]-MK-801 binding testplotted against concentration.

Further research with respect to MRZ 2/616,1-amino-1,3,5-trimethylcyclohexane, showed it to be a 1:2 mixture of theisomers 1,cis-3,cis-5-trimethyl- and1,trans-3,trans-5-trimethylcyclohexylamine, which was separated inconventional manner into the individual pure enantiomeric forms MRZ2/680, the 1-amino-1(trans),3(trans),5-trimethylcyclohexane and MRZ2/681, 1-amino-1(cis),3(cis),5-trimethylcyclohexane as the hydrochlorideand hydrochloride hydrate, respectively.

In addition, MRZ 2/632 and MRZ 2/633 were separated in conventionalmanner into their pure enantiomeric forms, MRZ 2/682 and MRZ 2/683,respectively 1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane asthe hydrochloride and1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane as thehydrochloride hydrate. All of these compounds, and their pureenantiomers, MRZ 2/616, MRZ 2/680, MRZ 2/681, MRZ 2/682 and MRZ 2/683,appear in the foregoing Tables along with the pharmacological datarelating thereto.

The analytical certificates for these five (5) MRZ compounds follow:

MRZ 2/616 ##STR7## 1,cis-3,cis-5-Trimethyl- and1,trans-3,trans-5-trimethylcyclohexylamines hydrochlorides (-1:2)

Molecular formula: C₉ H₁₉ N*HCl Molecular weight: 177.7 Melting point:280-282° C. PMR spectrum: (CDCl₃, TMS) δ: 0.90 (6H, d, 5.5 Hz, 3,5-CH₃);1.0-1.3 (2H, m, 4-CH₂); 1.44 and 1.50 (3 H, both s, 1-CH₃); 1.55-2.4(6H, m, 2-CH₂, 6-CH₂, 3-CH and 5-CH) and 8.25 ppm (3H, br s, NH₃ ⁺).Solubility: soluble in water, chloroform. Elemental analysis: Found (%)C, 60.7; H, 11.5; N, 7.7. Calculated (%) C, 60.8; H, 11.3; N, 7.9.Impurities: less than 2.5% (for free amine: GC, MN-OV-1 (Fused Silica),25 m*0.53 mm, d_(f) =1.0 μ, 50-270° C. (10° C./min)).

MRZ 2/680 ##STR8## 1,trans-3,trans-5-TrimethylcyclohexylamineHydrochloride

Molecular formula: C₉ H₁₉ N*HCl Molecular weight: 177.7 Meltingpoint: >280° C. PMR spectrum: (CDCl₃, TMS) δ: 0.89 (6H, d, J=6 Hz,3,5-CH₃); 0.9-2.3 (8H₁, m, ring protons); 1.44 (3H, s, 1-CH₃) and 8.25ppm (3H, br s, NH₃ ⁺). Solubility: soluble in water, chloroform.Elemental analysis: Found (%) C, 60.7; H, 11.7; N, 7.7. Calculated (%)C, 60.8; H, 11.3; N, 7.9. Impurities: 2% (for free amine: GC, MN-OV-1(Fused Silica), 25 m*0.53 mm, d_(f) =1.0 μ, 50-270° C. (10° C/min)).

MRZ 2/681 ##STR9## 1,cis-3,cis-5-Trimethylcyclohexylamine hydrochlorideHydrate

Molecular formula; C₉ H₁₉ N*HCl*H₂ O Molecular weight: 195.7 Meltingpoint; 237-238° C. PMR spectrum: (CDCl₃, TMS) δ: 0.89 (6H, d, J=5.5 Hz,3,5-CH₃); 0.9-2.3 (8H, m, ring protons); 1.47 (3H, s, 1-CH₃) and 8.3 ppm(3H, br s, NH₃ ⁺). Solubility: soluble in water, chloroform. Elementalanalysis: Found (%) C, 55.3; H, 11.6; N, 7.1. Calculated (%) C, 55.2; H,11.3; N, 7.2. Impurities: 1.5% (for free amine: GC, MN-OV-1 (FusedSilica), 25 m*0.53 mm, d_(f) =1.0 μ, 50-270° C. (10° C/min)).

MRZ 2/682 ##STR10## (1R, 5S)trans-3-Ethyl-1,5,5-trimethylcyclohexylamine Hydrochloride

Molecular formula; C₁₁ H₂₃ N*HCl Molecular weight: 205.8 Meltingpoint: >280° C. (subl.) PMR spectrum: (CDCl₃, TMS) δ: 0.8-1.0 (m) and0.91 (s, total 6H, 5-CH_(3eq) and CH₃ -ethyl); 1.22 (3H, s ,5-CH_(3ax));1.44 (3H, s, 1-CH₃); 1.0-2.3 (9H, m, ring protons and CH₂ -ethyl) and8.2 ppm (3H, br s, NH₃ ⁺). Solubility; soluble in chloroform, poorsoluble in water. Elemental analysis: Found (%) C, 64.2; H, 11.9, N,6.6. Calculated (%) C, 64.2; H, 11.8; N, 6.8. Impurities: less than 1%(for free amine: GC, MN-OV-1 (Fused Silica), 25 m*0.53 mm, d_(f) =1.0 μ,50-270° C. (10° C/min)).

M MRZ 2/683 ##STR11## (1S, 5S)cis-3-Ethyl-1,5,5-trimethylcyclohexylamine Hydrochloride Hydrate

Molecular formula: C₁₁ H₂₃ N*HCl*H₂ O Molecular weight: 223.8 Meltingpoint: 243-245° C. PMR spectrum: (CDCl₃, TMS) δ: 0.88 (m) and 0.96 (s,total 9H, 5-CH₃ and CH₃ -ethyl); 1.50 (3H, s, 1-CH₃); 1.0-2.15 (9H, m,ring protons and CH₂ -ethyl) and 8.35 ppm (3H, br s, NH₃ ⁺). Solubility:soluble in chloroform, poor soluble in water. Elemental analysis: Found(%) C, 59.9; H, 11.8; N, 6.2. Calculated (%) C, 59.0; H, 11.6, N, 6.3.Impurities: less than 1% (for free amine: GC, MN-OV-1 (Fused Silica), 25m*0.53 mm, d_(f) =1.0 μ, 50-270° C. (10° C/min)).

In conclusion, from the foregoing, it is apparent that the presentinvention provides novel, valuable, and unpredictable applications anduses of the compounds of the present invention, which compounds comprisethe active principle according to the present invention, as well asnovel pharmaceutical compositions thereof and methods of preparationthereof and of treating therewith, all possessed of the foregoing morespecifically-enumerated characteristics and advantages.

The high order of activity of the active agent of the present inventionand compositions thereof, as evidenced by the tests reported, isindicative of utility based on its valuable activity in human beings aswell as in lower animals. Clinical evaluation in human beings has notbeen completed, however. It will be clearly understood that thedistribution and marketing of any compound or composition falling withinthe scope of the present invention for use in human beings will ofcourse have to be predicated upon prior approval by governmentalagencies, such as the U.S. Federal Food and Drug administration, whichare responsible for and authorized to pass judgment on such questions.

Conclusions

The present 1-amino-alkylcyclohexanes represent a novel class ofsystemically-active, uncompetitive NMDA receptor antagonists with rapidblocking/unblocking kinetics and strong voltage-dependency. In view oftheir relatively low potency and associated rapid kinetics, they will beuseful therapeutics in a wide range of CNS disorders which involvedisturbances of glutamatergic transmission.

These compounds accordingly find application in the treatment of thefollowing disorders of a living animal body, especially a human. 1.Acute excitotoxicity such as ischaemia during stroke, trauma, hypoxia,hypoglycemia, and hepatic encephalopathy. 2. Chronic neurodegenerativediseases such as Alzheimer's disease, vascular dementia, Parkinson'sdisease, Huntington's disease, multiple sclerosis, amyotrophic lateralsclerosis, AIDS-neurode-generation, olivopontocerebellar atrophy,Tourette's syndrome, motor neurone disease, mitochondrial dysfunction,Korsakoff syndrome, Creutzfeldt-Jakob disease. 3. Other disordersrelated to long term plastic changes in the central nervous system suchas chronic pain, drug tolerance, dependence and addiction (e.g.,opioids, cocaine, benzodiazepines, and alcohol). 4. Epilepsy, tardivedyskinesia, schizophrenia, anxiety, depression, acute pain, spasticity,and tinnitus. 5. In addition, as already stated, due at least in part totheir amine substituent, the compounds of the present invention are alsoeffective in non-NMDA indications, exhibiting immunomodulatory activity,antimalaria potency, anti-Borna virus activity, and anti-Hepatitis Cactivity.

It is to be understood that the invention is not to be limited to theexact details of operation, or to the exact compositions, methods,procedures, or embodiments shown and described, as obvious modificationsand equivalents will be e apparent to one skilled in the art, and theinvention is therefore to be limited only by the full scope which can belegally accorded to the appended claims.

REFERENCES

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We claim:
 1. A method-of-treating a living animal for alleviation of acondition which is alleviated by an NMDA receptor antagonist, or for itsimmunomodulatory, antimalarial, anti-Borna virus, or anti-Hepatitis Ceffect, comprising the step of administering to the said living animalan amount of a 1-aminoalkylcyclohexane compound selected from the groupconsisting of those of the formula ##STR12## wherein R* is --(CH₂)_(n),(CR⁶ R⁷)_(m) --NR⁸ R⁹ wherein n+m=0, 1, or 2 wherein R¹ through R⁷ areindependently selected from the group consisting of hydrogen andlower-alkyl (1-6C), wherein R⁸ and R⁹ are independently selected fromthe group consisting of hydrogen and lower-alkyl (1-6C) or togetherrepresent lower-alkylene --(CH₂)_(x) -- wherein x is 2 to 5, inclusive,and optical isomers, enantiomers, hydrates, andpharmaceutically-acceptable salts thereof, which is effective for thesaid purpose.
 2. A method of claim 1 wherein R¹ through R⁵ are methyl.3. A method of claim 1 wherein R¹ is ethyl.
 4. A method of claim 1wherein R² is ethyl.
 5. A method of claim 1 wherein R³ is ethyl.
 6. Amethod of claim 1 wherein R⁴ is ethyl.
 7. A method of claim 1 wherein R⁵is ethyl.
 8. A method of claim 1 wherein R⁵ is propyl.
 9. A method ofclaim 1 wherein R⁶ or R⁷ is methyl.
 10. A method of claim 1 wherein R⁶or R⁷ is ethyl.
 11. A method of claim 1 wherein the compound is selectedfrom the group consisting of1-amino-1,3,5-trimethylcyclohexane,1-amino-1(trans),3(trans),5-trimethylcyclohexane,1-amino-1(cis),3(cis),5-trimethylcyclohexane,1-amino-1,3,3,5-tetramethylcyclohexane,1-amino-1,3,3,5,5-pentamethylcyclohexane,1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane,1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane,1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane,1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane,1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, andN-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine, and optical isomers,enantiomers, hydrates and pharmaceutically-acceptable salts of any ofthe foregoing.
 12. A method of claim 1 wherein the compound isadministered in the form of a pharmaceutical composition thereofcomprising the compound in combination with one or morepharmaceutically-acceptable diluents, excipients, or carriers.